+

US8088763B2 - Cyclohexyl-1, 4-diamine compounds - Google Patents

Cyclohexyl-1, 4-diamine compounds Download PDF

Info

Publication number
US8088763B2
US8088763B2 US11/594,963 US59496305A US8088763B2 US 8088763 B2 US8088763 B2 US 8088763B2 US 59496305 A US59496305 A US 59496305A US 8088763 B2 US8088763 B2 US 8088763B2
Authority
US
United States
Prior art keywords
cyclohexyl
benzyl
dimethylamino
succinamide
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US11/594,963
Other versions
US20070112007A1 (en
Inventor
Corinna Sundermann
Bernd Sundermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Assigned to GRUENENTHAL GMBH reassignment GRUENENTHAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SUNDERMANN, BERND, SUNDERMANN, CORINNA
Publication of US20070112007A1 publication Critical patent/US20070112007A1/en
Application granted granted Critical
Publication of US8088763B2 publication Critical patent/US8088763B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/41—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • the present invention relates to cyclohexyl-1,4-diamine compounds, processes for the production thereof, pharmaceutical compositions containing these compounds, methods of producing pharmaceutical compositions including these compounds and related methods of treating or inhibiting certain diseases or conditions.
  • ⁇ -opioids such as morphine are very effective in the treatment of strong to very strong pain and are of great importance for the treatment of pain.
  • further opioid receptors in particular the ORL1 receptor
  • pure ⁇ -opioids also have undesirable side effects, such as obstipation and respiratory depression, and may also lead to addiction.
  • the opioid receptors ⁇ , ⁇ and ORL1 are also involved in the state of pain (Opioids: Introduction, pp. 127-150, Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).
  • the ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory formation (Manabe et al, Nature, 394, 1997, pp. 577-581), Hörconf [Hearing capacity] (Nishi et al, EMBO J., 16, 1997, pp. 1858-1864) and numerous further processes. In a synopsis by Calo et al (Br. J. Pharmacol., 129, 2000, 1261-1283) there is an overview of the indications or biological procedures, in which the ORL1 receptor plays a part or could highly probably play a part.
  • analgesics stimulation and regulation of nutrient absorption, effect on ⁇ -agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing the cardiovascular system, triggering an erection, diuresis, anti-natriuresis, electrolyte balance, arterial blood pressure, water-retention disorders, intestinal motility (diarrhoea), relaxation of the respiratory tract, micturation reflex (urinary incontinence).
  • agonists and antagonists such as anoretics, analgesics (also when administered with opioids) or nootropics will also be discussed.
  • An object of the present invention was to provide pharmaceutical compositions which act on the opioid receptor system and are thus suitable for pharmaceutical compositions, in particular for the treatment of the various diseases associated with this system according to the prior art and for use in the indications mentioned therein.
  • the compounds are also intended to influence noradrenalin and serotonin re-uptake
  • the invention therefore relates to substituted cyclohexyl-1,4-diamine derivatives of general formula I,
  • n 1, 2, 3, 4 or 5
  • R 1 and R 2 independently of one another represent H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-5 alkyl; respectively singly or multiply substituted or unsubstituted C 3-8 -cycloalkyl; or respectively singly or multiply substituted or unsubstituted aryl, C 3-8 cycloalkyl or heteroaryl bound by C 1-3 alkyl;
  • radicals R1 and R2 together represent CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6,
  • R 10 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-5 alkyl respectively singly or multiply substituted or unsubstituted C 3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C 3-8 cycloalkyl or heteroaryl bound by C 1-3 alkyl; respectively substituted or unsubstituted C(O)phenyl, C(O)heteroaryl, C(O)C 1-5 alkyl;
  • R 3 represents respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-5 alkyl; respectively singly or multiply substituted or unsubstituted C 3-8 cycloalkyl; respectively unsubstituted or singly or multiply substituted aryl or heteroaryl; respectively unsubstituted or singly or multiply substituted aryl, heteroaryl or C 3-8 cycloalkyl bound by a C 1-3 alkyl group;
  • R 4 represents —(CR 6 R 7 ) p R 8 ,
  • R 6 represents H or respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C 1-5 alkyl
  • R 7 represents H, respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C 1-5 alkyl or COOR 9 ,
  • R 8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C 1-6 alkyl, respectively unsubstituted or singly or multiply substituted C 3-8 cycloalkyl, aryl or heteroaryl,
  • R 9 represents H or C 1-5 alkyl
  • R 5 represents H or —(CH 2 ) l R 8 ,
  • R 4 represents CH 2 CHR 14 OCHR 14 CH 2 , CH 2 CH 2 SCH 2 CH 2
  • R 11 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-5 alkyl; respectively saturated or unsaturated, singly or multiply substituted or unsubstituted C 3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C 1-3 alkyl;
  • R 12 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-5 alkyl; OH; unsubstituted or singly or multiply substituted C(O)phenyl; respectively singly or multiply substituted or unsubstituted C 3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C 3-8 cycloalkyl or heteroaryl bound by C 1-3 alkyl;
  • R 13 represents H or OH or together with R 12 via the same C atom (spiro compound) or an adjacent C atom forms a five-membered or six-membered ring which may contain heteroatoms, be saturated or unsaturated, substituted or unsubstituted and/or be part of a polycyclic system;
  • R 14 represents H or respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-3 alkyl;
  • the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
  • the compounds according to the invention exhibit good binding to the ⁇ receptor and the ORL1 receptor, but also to other opioid receptors. Surprisingly it has been found that the compounds are also good inhibitors of noradrenalin and serotonin re-uptake. They are therefore also suitable for treating depression and/or bulimia and/or anorexia and/or catalepsy and/or anxiolysis and/or increasing alertness and/or libido.
  • C 1-6 alkyl comprise, in the context of this invention, acyclic saturated or unsaturated hydrocarbon radicals, which may be branched or straight-chained and unsubstituted or singly or multiply substituted, with 1, 2, 3, 4, 5 or 6 C atoms or 1, 2, 3, 4 or 5 C atoms or 1, 2 or 3 C atoms, i.e.
  • Alkenyls have at least one C—C double bond and alkynyls at least one C—C treble bond.
  • Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 2,3-dimethylbutyl; ethylenyl (vinyl), ethynyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), propynyl (—CH—C ⁇ CH, —C ⁇ C—CH 3 ), 1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butynyl, pentenyl and pentynyl, hexenyl and hexynyl.
  • cycloalkyl or “C 3-8 cycloalkyl” denotes cyclic hydrocarbons with 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons may be saturated or unsaturated (but not aromatic), unsubstituted or singly or multiply substituted.
  • cycloalkyl the term also comprises saturated or unsaturated (but not aromatic) cycloalkyls, in which one or two carbon atoms are replaced by an S, N or O heteroatom.
  • C 3-8 cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.
  • (CH 2 ) 3-6 denotes —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 — and CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —.
  • aryl denotes carbocyclic ring systems comprising at least one aromatic ring, but without a heteroatom in only one of the rings, inter alia phenyls, naphthyls and phenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.
  • the aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical can be present unsubstituted or singly or multiply substituted, wherein the aryl substituents may be the same or different and in any desired and possible position of the aryl. Phenyl or naphthyl radicals are particularly advantageous.
  • heteroaryl represents a 5-, 6- or 7-membered cyclic aromatic radical, which contains at least 1 heteroatom, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same or different and the heterocycle may be unsubstituted or singly or multiply substituted; in the case of substitution on the heterocycle, the substituents may be the same or different and in any desired and possible position of the heteroaryl.
  • the heterocycle may also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulphur.
  • heteroaryl radical is selected from the group comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the binding with the compounds of general
  • the term “substituted”, according to this invention, denotes substitution of one or more hydrogen radicals by F, CI, Br, I, —CN, ⁇ O, ⁇ S, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-OH, N(alkyl) 2 , N(alkyl-aryl) 2 , N(alkyl-heteroaryl) 2 , N(cycloalkyl) 2 , N(alkyl-OH) 2 , NH(C ⁇ O)alkyl, NH(C ⁇ O)aryl, NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, NH 2 , S
  • a substituent may optionally also be substituted for its part; thus —O-alkyl also includes inter alia —O—CH 2 —CH 2 —O—CH 2 —CH 2 —OH.
  • aryl “heteroaryl” and “cycloalkyl”, according to this invention, “singly or multiply substituted” denotes the single or multiple, for example double, treble, quadruple or quintuple, substitution of one or more hydrogen atoms of the ring system by F, CI, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N(alkyl) 2 , N(alkyl-aryl) 2 , N(alkyl-heteroaryl) 2 , N(cycloalkyl) 2 , N(alkyl-OH) 2 , NO 2 , SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-alkyl
  • salt denotes any form of the active ingredient according to this invention in which it assumes or is charged with an ionic form and is coupled to a counter ion (a cation or anion) or is in solution.
  • This also includes complexes of the active ingredient with other molecules and ions, in particular complexes complexed by ionic interactions.
  • physiologically acceptable salts in particular physiologically acceptable salts with cations or bases and physiologically acceptable salts with anions or acids or else a salt formed with a physiologically acceptable acid or physiologically acceptable cation.
  • physiologically acceptable salt with anions or acids denotes, in the context of this invention, salts of at least one of the compounds according to this invention—usually protonated, for example on nitrogen—as a cation with at least one anion which are physiologically acceptable—in particular when applied to humans and/or mammals.
  • this denotes, in particular, the salt formed with a physiologically acceptable acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically acceptable—in particular when applied to humans and/or mammals.
  • physiologically acceptable salts of specific acids include salts of: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -lipoic acid, acetyl glycine, phosphoric acid, maleic acid, malonic acid, hippuric acid and/or aspartic acid.
  • the hydrochloride salt, the citrate and the hemicitrate are particularly preferred.
  • salt formed with a physiologically acceptable acid denotes salts of the respective active ingredient with inorganic or organic acids which are physiologically acceptable—in particular when applied to humans and/or mammals.
  • the hydrochloride and the citrate are particularly preferred.
  • physiologically acceptable acids include: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -lipoic acid, acetyl glycine, hippuric acid and/or aspartic acid.
  • physiologically acceptable salt with cations or bases denotes, in the context of this invention, salts of at least one of the compounds according to this invention—usually a (deprotonated) acid—as an anion with at least one, preferably inorganic, cation, which are physiologically acceptable, in particular when applied to humans and/or mammals.
  • the salts of the alkali and alkaline-earth metals are particularly preferred, but also ammonium salts, in particular (mono-) or (di-) sodium, (mono-) or (di-)potassium, magnesium or calcium salts.
  • salt formed with a physiologically acceptable cation denotes, according to this invention, salts of at least one of the respective compounds as an anion with at least one inorganic cation, which are physiologically acceptable, in particular when applied to humans and/or mammals.
  • the salts of the alkali and alkaline-earth metals are particularly preferred, but also ammonium salts, in particular (mono-) or (di-) sodium, (mono-) or (di-)potassium, magnesium or calcium salts.
  • R 1 and R 2 independently of one another represent H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-5 alkyl;
  • radicals R 1 and R 2 together form a ring and represent CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 or (CH 2 ) 3-6 ,
  • R 10 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C 1-5 alkyl.
  • substituted cyclohexyl-1,4-diamine derivatives wherein R 1 and R 2 independently of one another represent CH 3 or H, wherein R 1 and R 2 do not simultaneously represent H, or R 1 and R 2 represent CH 2 CH 2 OCH 2 CH 2 or (CH 2 ) 6 .
  • R 3 represents respectively unsubstituted or singly or multiply substituted cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl; respectively unsubstituted or singly or multiply substituted C 5-6 cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or
  • R 3 represents respectively unsubstituted or singly or multiply substituted phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxanyl, pyridyl, pyrimidyl, pyrazinyl or benzothiophenyl; respectively unsubstituted or singly or multiply substituted phenyl, furyl or thiophenyl bound by a saturated, unbranched C 1-2 alkyl group.
  • R 3 represents respectively substituted or unsubstituted phenyl, thiophenyl, pyridyl or benzyl, particularly preferably 4-methylbenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-methylbenzyl, benzyl, phenyl, thiophenyl and 3-fluorophenyl.
  • R 8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C 1-6 alkyl; respectively unsubstituted or singly or multiply substituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyrrolidinyl, tetrahydrofuryl, piperazinyl, pyridyl, pyrrolyl, pyrazinyl or pyrimi
  • substituted cyclohexyl-1,4-diamine derivatives from the group comprising
  • the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
  • the substances according to the invention act, for example, on the ORL1 receptor that is relevant in connection with various diseases, so they are suitable as a pharmaceutical active ingredient in a pharmaceutical composition.
  • the invention therefore further relates to pharmaceutical compositions containing at least one substituted cyclohexyl carboxylic acid derivative according to the invention, and optionally suitable additives and/or auxiliaries and/or optionally further active ingredients.
  • compositions according to the invention contain, in addition to at least one substituted cyclohexyl-1,4-diamine derivative according to the invention, optionally suitable additives and/or auxiliaries, therefore also excipients, fillers, solvents, diluents, dyes and/or binders and can be administered as liquid pharmaceutical compositions in the form of injection solutions, drops or syrups, as semi-solid pharmaceutical compositions in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • auxiliaries etc.
  • compositions depend on whether the pharmaceutical composition is to be applied orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral application, solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative applications.
  • Substituted cyclohexyl-1,4-diamine derivatives according to the invention in a deposit, in dissolved form or in a plaster, optionally with the addition of agents to promote skin penetration, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the substituted cyclohexyl-1,4-diamine derivatives according to the invention after a delay.
  • the substituted cyclohexyl-1,4-diamine derivatives according to the invention may also be applied in the form of parenteral long-acting repositories such as implants or implanted pumps.
  • further active ingredients known to the person skilled in the art can be added to the pharmaceutical compositions according to the invention.
  • the amount of active ingredient to be administered to the patient varies as a function of the weight of the patient, the method of application, the indication and the severity of the illness. Conventionally, 0.00005 to 50 mg/kg, preferably 0.01 to 5 mg/kg, of at least one substituted cyclohexyl-1,4-diamine derivative according to the invention are applied.
  • the pharmaceutical composition contains a further active ingredient, in particular an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
  • an opioid preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
  • a contained substituted cyclohexyl-1,4-diamine derivative according to the invention is in the form of a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
  • substituted cyclohexyl-1,4-diamine derivatives according to the invention can be used for producing a pharmaceutical composition for the treatment of pain, in particular acute, neuropathic or chronic pain.
  • the invention therefore further relates to the use of a substituted cyclohexyl-1,4-diamine derivative according to the invention for producing a pharmaceutical composition for treating pain, in particular acute, visceral, neuropathic or chronic pain.
  • the invention further relates to the use of a substituted cyclohexyl-1,4-diamine derivative according to the invention for the production of a pharmaceutical composition for the treatment of anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, catalepsy, general cognitive dysfunction, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol- and/or drug- and/or medicine abuse and/or dependency, sexual dysfunction, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing difficulties, deficient intestine motility, impaired absorption of nutrients, anorexia, obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinence, or as a muscle relaxant, anti-convulsive or anaesthetic or for co-administration in treatment with an opioid analgesic or anaesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulation of motor activity, for modulation of
  • a substituted cyclohexyl-1,4-diamine derivative used is in the form of a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
  • the invention further relates to a process for the treatment, in particular in one of the above-mentioned indications, of a non-human mammal or human, which or who requires treatment of pain, in particular chronic pain, by administration of a therapeutically effective dose of a substituted cyclohexyl-1,4-diamine derivative according to the invention, or of a pharmaceutical composition according to the invention.
  • the invention further relates to a process for producing the substituted cyclohexyl-1,4-diamine derivatives according to the invention, as stated in the following description and examples.
  • radicals R 01 and R 02 have the meaning given for compounds according to the invention of formula I for R 1 and R 2 and, in addition, independently of one another can represent a protecting group.
  • the remaining radicals have the meaning indicated in formula I:
  • the process according to the invention involves linking substituted cyclohexane-1,4-diamines (WO 02090317) via anhydrides, open-chain dicarboxylic acids or preferably the activated analogues thereof, in particular the acid halides thereof, with further primary or secondary amines and thus converting them into compounds according to the invention.
  • anhydrides are initially opened with a cyclohexane-1,4-diamine or a primary or secondary amine to form the corresponding semi-amides, before being reacted in the second step to the diamide by a complementary primary or secondary amine or a cyclohexane-1,4-diamine in the presence of dehydrating agents.
  • a carboxylic acid equivalent for example acid chloride or active ester.
  • the reactions with anhydrides preferably take place in polar or non-polar aprotic solvents such as DMF, DMSO, diethyl ether, diisopropylether, THF, toluene, dichloromethane or acetonitrile at temperatures between ⁇ 20 and +110° C., preferably between ⁇ 10 and +40° C.
  • polar or non-polar aprotic solvents such as DMF, DMSO, diethyl ether, diisopropylether, THF, toluene, dichloromethane or acetonitrile
  • polar or non-polar aprotic solvents to which an organic or inorganic auxiliary base, preferably tertiary amines such as triethylamine, diisopropylethylamine or DMAP, has been added, are also used.
  • auxiliary base preferably tertiary amines such as triethylamine, diisopropylethylamine or DMAP
  • pyridine for example, is also suitable as a base and as a solvent.
  • acid chlorides are reacted with amines at ⁇ 10 and +40° C. in dichloromethane or chloroform in the presence of triethylamine or pyridine and optionally catalytic amounts of DMAP.
  • ether denotes diethyl ether, “EE” ethyl acetate and “DCM” dichloromethane.
  • equivalent denotes amount of substance equivalent, “mp.” melting point or melting range, “decomp.” decomposition, “RT” room temperature, “abs.” absolute (anhydrous), “rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol. %” volume percent, “m %” mass percent and “M” is a concentration in mol/l.
  • Table 1 cites the carboxylic acids used for the last step for the examples.
  • Example Name of example compound 1 N-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]- N′-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-succinamide 2 N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-oxo-tetrahydro-furan-3- yl)-succinamide 3 N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3,3-diphenyl-propyl)- succinamide 4 N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-[4-(7-methoxy-
  • Example 341 357 mg of the polar diastereoisomer of N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-yl-methylsuccinic acid amide were also obtained, which, dissolved in 25 ml 2-butanone, were converted into the corresponding hydrochloride by adding 14.4 ⁇ l water and 100 ⁇ l chlorotrimethylsilane (230 mg of white solid, mp. 186-188° C.).
  • Example 341 0.95 mg 4-[2-(2-fluorophenyl)ethylcarbamoyl]butyric acid and 0.87 1-benzyl-N,N-dimethylcyclohexane-1,4-diamine were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.50 g 1-hydroxybenzotriazole and the crude product (1.65 g yellow solid) similarly isolated.
  • Example 343 260 mg of the polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide were also obtained, which were dissolved in 5 ml 2-butanone and 45 ml ethyl acetate and converted into the corresponding hydrochloride by adding 10 ⁇ l water and 71 ⁇ l chlorotrimethylsilane (110 mg of vitreous solid).
  • Example 341 As described for Example 341, 0.96 mg N-[2-(4-chlorophenyl)ethyl]succinic acid and 1.0 g 4-(3-chlorobenzyl)-4-dimethylaminocyclohexanone were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.5 g 1-hydroxybenzotriazole and the crude product (2.23 g yellow solid) similarly isolated.
  • Example 345 360 mg of the polar diastereoisomer of N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]succinic acid amide were also obtained, which were dissolved in 25 ml 2-butanone and 10 ml ethyl acetate and converted into the corresponding hydrochloride by adding 12.5 ⁇ l water, 88 ⁇ l chlorotrimethylsilane and 10 ml diisopropylether (236 mg of white solid, mp 186-187.5° C.).
  • Example 341 As described for Example 341, 0.87 mg 4-[2-(4-chlorophenyl)ethyl-carbamoyl]butyric acid and 1.0 g 4-benzyl-4-dimethylaminocyclohexanone were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.5 g 1-hydroxybenzotriazole and the crude product (1.80 g) similarly isolated.
  • the cyclohexane derivatives of general formula I were examined in a receptor binding assay with 3 H-nociceptin/orphanin FQ with membranes of recombinant CHO-ORL1 cells.
  • This test system was carried out according to the methods presented by Ardati et al (Mol. Pharmacol., 51, 1997, pp. 816-824).
  • the concentration of 3 H-nociceptin/orphanin FQ was 0.5 nM in these tests.
  • the binding assays were carried out with 20 ⁇ g membrane protein per 200 ⁇ l batch in 50 mM Hepes, pH 7.4, 10 mM MgCl 2 and 1 mM EDTA.
  • the binding with the ORL1 receptor was determined by using 1 mg WGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubation of the batch for one hour at RT and subsequent measurement in the Trilux scintillation counter (Wallac, Finland).
  • the receptor affinity for human p-opiate receptor was determined in a homogenous batch in microtitre plates.
  • dilution series of the respective substituted cyclohexyl-1,4-diamine derivative to be tested were incubated with a receptor membrane preparation (15-40 ⁇ g protein per 250 ⁇ l incubation batch) of CHO-K1 cells, which express the human ⁇ -opiate receptor (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [ 3 H]-naloxone (NET719, NEN, Zaventem, Belgium) and 1 mg WGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 ⁇ l for 90 minutes at room temperature.
  • IC 50 inhibition concentrations which bring about a 50% displacement of the radioactive ligand, were partially calculated by taking as a basis the percentage displacement by various concentrations of the compounds of general formula I to be tested. Ki values for the test substances were obtained as a result of conversion by means of the Cheng-Prusoff equation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Vascular Medicine (AREA)
  • Obesity (AREA)
  • Nutrition Science (AREA)
  • Anesthesiology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel cyclohexyl-1,4-diamine compounds corresponding to formula I,
Figure US08088763-20120103-C00001
processes for the production thereof, pharmaceutical compositions containing these compounds, methods of producing pharmaceutical compositions including these compounds and related methods of treating or inhibiting certain diseases or conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of International patent application Serial No. PCT/EP2005/004913 filed May 6, 2005 which claims benefit to German patent application Serial No. 10 2004 023 522.8 filed May 10, 2004, the entire disclosures of which are hereby incorporated in their entirety.
FIELD OF THE INVENTION
The present invention relates to cyclohexyl-1,4-diamine compounds, processes for the production thereof, pharmaceutical compositions containing these compounds, methods of producing pharmaceutical compositions including these compounds and related methods of treating or inhibiting certain diseases or conditions.
BACKGROUND OF THE INVENTION
The treatment of chronic and non-chronic pain conditions has great importance in medicine. There is a worldwide need for effective methods of treating pain. The urgent need for action for patient-oriented and purposeful treatment of chronic and non-chronic pain conditions, this being taken to mean the successful and satisfactory treatment of pain for the patient, is documented in the large number of scientific papers which have recently appeared in the field of applied analgesics and fundamental research work on nociception.
Conventional μ-opioids such as morphine are very effective in the treatment of strong to very strong pain and are of great importance for the treatment of pain. However, it may be advantageous if, in addition to the μ-opioid receptor, further opioid receptors, in particular the ORL1 receptor, are affected, since pure μ-opioids also have undesirable side effects, such as obstipation and respiratory depression, and may also lead to addiction. The opioid receptors δ, κ and ORL1 are also involved in the state of pain (Opioids: Introduction, pp. 127-150, Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).
It is also known that influencing of serotonin and/or noradrenalin re-uptake can be beneficial to the effects and side effects of opioids (Example: Tramadol, see Opioids with Clinical Relevance: Tramadol, 228-230 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory formation (Manabe et al, Nature, 394, 1997, pp. 577-581), Hörvermögen [Hearing capacity] (Nishi et al, EMBO J., 16, 1997, pp. 1858-1864) and numerous further processes. In a synopsis by Calo et al (Br. J. Pharmacol., 129, 2000, 1261-1283) there is an overview of the indications or biological procedures, in which the ORL1 receptor plays a part or could highly probably play a part. Mentioned inter alia are: analgesics, stimulation and regulation of nutrient absorption, effect on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing the cardiovascular system, triggering an erection, diuresis, anti-natriuresis, electrolyte balance, arterial blood pressure, water-retention disorders, intestinal motility (diarrhoea), relaxation of the respiratory tract, micturation reflex (urinary incontinence). The use of agonists and antagonists such as anoretics, analgesics (also when administered with opioids) or nootropics will also be discussed.
Structurally related compounds which have an affinity with the ORL1 receptor are known from the prior art (WO 02090317). The effect on noradrenalin and serotonin re-uptake has not previously been described for this structural class.
SUMMARY OF THE INVENTION
An object of the present invention was to provide pharmaceutical compositions which act on the opioid receptor system and are thus suitable for pharmaceutical compositions, in particular for the treatment of the various diseases associated with this system according to the prior art and for use in the indications mentioned therein. The compounds are also intended to influence noradrenalin and serotonin re-uptake
The invention therefore relates to substituted cyclohexyl-1,4-diamine derivatives of general formula I,
Figure US08088763-20120103-C00002
wherein
n represents 1, 2, 3, 4 or 5
R1 and R2 independently of one another represent H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; respectively singly or multiply substituted or unsubstituted C3-8-cycloalkyl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
or the radicals R1 and R2 together represent CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6,
wherein R10 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl respectively singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl; respectively substituted or unsubstituted C(O)phenyl, C(O)heteroaryl, C(O)C1-5 alkyl;
R3 represents respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; respectively singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively unsubstituted or singly or multiply substituted aryl or heteroaryl; respectively unsubstituted or singly or multiply substituted aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkyl group;
R4 represents —(CR6R7)pR 8,
wherein p represents 0, 1, 2, 3 or 4
R6 represents H or respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl,
R7 represents H, respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl or COOR9,
or R6 and R7 form a ring (CH2)kCHR8(CH2)m, where k=1, 2, 3 and m=1, 2
R8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl, respectively unsubstituted or singly or multiply substituted C3-8 cycloalkyl, aryl or heteroaryl,
R9 represents H or C1-5 alkyl
R5 represents H or —(CH2)lR8,
wherein l represents 1, 2 or 3,
or together with R4 represents CH2CHR14OCHR14CH2, CH2CH2SCH2CH2
CH2CH2NR11CH2CH2, (CR12R13)3-6 or
Figure US08088763-20120103-C00003
wherein R11 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; respectively saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
R12 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; OH; unsubstituted or singly or multiply substituted C(O)phenyl; respectively singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
and R13 represents H or OH or together with R12 via the same C atom (spiro compound) or an adjacent C atom forms a five-membered or six-membered ring which may contain heteroatoms, be saturated or unsaturated, substituted or unsubstituted and/or be part of a polycyclic system;
R14 represents H or respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-3 alkyl;
in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
The compounds according to the invention exhibit good binding to the μ receptor and the ORL1 receptor, but also to other opioid receptors. Surprisingly it has been found that the compounds are also good inhibitors of noradrenalin and serotonin re-uptake. They are therefore also suitable for treating depression and/or bulimia and/or anorexia and/or catalepsy and/or anxiolysis and/or increasing alertness and/or libido.
The terms “C1-6 alkyl”, “C1-5 alkyl” and “C1-3 alkyl” comprise, in the context of this invention, acyclic saturated or unsaturated hydrocarbon radicals, which may be branched or straight-chained and unsubstituted or singly or multiply substituted, with 1, 2, 3, 4, 5 or 6 C atoms or 1, 2, 3, 4 or 5 C atoms or 1, 2 or 3 C atoms, i.e. C1-6 alkanyls, C2-6 alkenyls and C2-6 alkynyls or C1-5 alkanyls, C2-5 alkenyls and C2-5 alkynyls or C1-3 alkanyls, C2-3 alkenyls and C2-3 alkynyl. Alkenyls have at least one C—C double bond and alkynyls at least one C—C treble bond. Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 2,3-dimethylbutyl; ethylenyl (vinyl), ethynyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propynyl (—CH—C≡CH, —C≡C—CH3), 1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butynyl, pentenyl and pentynyl, hexenyl and hexynyl.
For the purposes of this invention, the term “cycloalkyl” or “C3-8 cycloalkyl” denotes cyclic hydrocarbons with 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons may be saturated or unsaturated (but not aromatic), unsubstituted or singly or multiply substituted. With respect to cycloalkyl, the term also comprises saturated or unsaturated (but not aromatic) cycloalkyls, in which one or two carbon atoms are replaced by an S, N or O heteroatom. C3-8 cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.
The term “(CH2)3-6” denotes —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—CH2— and CH2—CH2—CH2—CH2—CH2—CH2—.
The term “aryl”, according to this invention, denotes carbocyclic ring systems comprising at least one aromatic ring, but without a heteroatom in only one of the rings, inter alia phenyls, naphthyls and phenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls. The aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical can be present unsubstituted or singly or multiply substituted, wherein the aryl substituents may be the same or different and in any desired and possible position of the aryl. Phenyl or naphthyl radicals are particularly advantageous.
The term “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic radical, which contains at least 1 heteroatom, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same or different and the heterocycle may be unsubstituted or singly or multiply substituted; in the case of substitution on the heterocycle, the substituents may be the same or different and in any desired and possible position of the heteroaryl. The heterocycle may also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulphur. It is preferred for the heteroaryl radical to be selected from the group comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the binding with the compounds of general structure I can be made via any desired and possible ring member of the heteroaryl radical.
In conjunction with “alkyl”, the term “substituted”, according to this invention, denotes substitution of one or more hydrogen radicals by F, CI, Br, I, —CN, ═O, ═S, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(alkyl-heteroaryl)2, N(cycloalkyl)2, N(alkyl-OH)2, NH(C═O)alkyl, NH(C═O)aryl, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-cycloalkyl, O-alkyl-OH, CHO, C(═O)C1-6 alkyl, C(═S)C1-6 alkyl, C(═O)aryl, C(═S)aryl, C(═O)C1-6 alkyl-aryl, C(═S)C1-6-alkyl aryl, C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(═O)NH2, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-cycloalkyl, C(═O)N(alkyl)2, C(═O)N(alkyl-aryl)2, C(═O)N(alkyl-heteroaryl)2, C(═O)N(cycloalkyl)2, SO-alkyl, SO2-alkyl, SO2NH2, SO3H, PO(O—C1-6 alkyl)2, cycloalkyl, aryl or heteroaryl, wherein the term “multiply substituted radicals” denotes radicals that have been multiply substituted, for example twice or three times, either on different or on the same atoms, for example three times on the same C atom, as in the case of CF3 or —CH2CF3, or in various positions, as in the case of —CH(OH)—CH═CH—CHCl2. Multiple substitution can take place with the same substituent or with different substituents. A substituent may optionally also be substituted for its part; thus —O-alkyl also includes inter alia —O—CH2—CH2—O—CH2—CH2—OH.
With respect to “aryl”, “heteroaryl” and “cycloalkyl”, according to this invention, “singly or multiply substituted” denotes the single or multiple, for example double, treble, quadruple or quintuple, substitution of one or more hydrogen atoms of the ring system by F, CI, Br, I, CN, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(alkyl-heteroaryl)2, N(cycloalkyl)2, N(alkyl-OH)2, NO2, SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-cycloalkyl, O-alkyl-OH, CHO, C(═O)C1-6 alkyl, C(═S)C1-6 alkyl, C(═O)aryl, C(═S)aryl, C(═O)—C1-6 alkyl-aryl, C(═S)C1-6 alkyl-aryl, C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(═O)NH2, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-cycloalkyl, C(═O)N(alkyl)2, C(═O)N(alkyl-aryl)2, C(═O)N(alkyl-heteroaryl)2, C(═O)N(cycloalkyl)2, S(O)-alkyl, S(O)-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO3H, CF3, ═O, ═S;
Figure US08088763-20120103-C00004
alkyl, cycloalkyl, aryl and/or heteroaryl; on one atom or optionally on different atoms (wherein a substituent can, in turn, optionally be substituted). Multiple substitution takes place here using the same or different substituents.
The term “salt” denotes any form of the active ingredient according to this invention in which it assumes or is charged with an ionic form and is coupled to a counter ion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes complexed by ionic interactions. In particular this denotes (and this is also a preferred embodiment of this invention) physiologically acceptable salts, in particular physiologically acceptable salts with cations or bases and physiologically acceptable salts with anions or acids or else a salt formed with a physiologically acceptable acid or physiologically acceptable cation.
The term “physiologically acceptable salt with anions or acids” denotes, in the context of this invention, salts of at least one of the compounds according to this invention—usually protonated, for example on nitrogen—as a cation with at least one anion which are physiologically acceptable—in particular when applied to humans and/or mammals. In the context of this invention this denotes, in particular, the salt formed with a physiologically acceptable acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically acceptable—in particular when applied to humans and/or mammals. Examples of physiologically acceptable salts of specific acids include salts of: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid, acetyl glycine, phosphoric acid, maleic acid, malonic acid, hippuric acid and/or aspartic acid. The hydrochloride salt, the citrate and the hemicitrate are particularly preferred.
The term “salt formed with a physiologically acceptable acid”, according to this invention, denotes salts of the respective active ingredient with inorganic or organic acids which are physiologically acceptable—in particular when applied to humans and/or mammals. The hydrochloride and the citrate are particularly preferred. Examples of physiologically acceptable acids include: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid, acetyl glycine, hippuric acid and/or aspartic acid.
The term “physiologically acceptable salt with cations or bases” denotes, in the context of this invention, salts of at least one of the compounds according to this invention—usually a (deprotonated) acid—as an anion with at least one, preferably inorganic, cation, which are physiologically acceptable, in particular when applied to humans and/or mammals. The salts of the alkali and alkaline-earth metals are particularly preferred, but also ammonium salts, in particular (mono-) or (di-) sodium, (mono-) or (di-)potassium, magnesium or calcium salts.
The term “salt formed with a physiologically acceptable cation” denotes, according to this invention, salts of at least one of the respective compounds as an anion with at least one inorganic cation, which are physiologically acceptable, in particular when applied to humans and/or mammals. The salts of the alkali and alkaline-earth metals are particularly preferred, but also ammonium salts, in particular (mono-) or (di-) sodium, (mono-) or (di-)potassium, magnesium or calcium salts.
For a preferred embodiment of the substituted cyclohexyl-1,4-diamine derivatives according to the invention
R1 and R2 independently of one another represent H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl;
or the radicals R1 and R2 together form a ring and represent CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6,
wherein R10 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl.
Particularly preferred are substituted cyclohexyl-1,4-diamine derivatives, wherein R1 and R2 independently of one another represent CH3 or H, wherein R1 and R2 do not simultaneously represent H, or R1 and R2 represent CH2CH2OCH2CH2 or (CH2)6.
Also preferred are substituted cyclohexyl-1,4-diamine derivatives, wherein
R3 represents respectively unsubstituted or singly or multiply substituted cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl; respectively unsubstituted or singly or multiply substituted C5-6 cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bound by a saturated, unbranched C1-2 alkyl group;
in particular
R3 represents respectively unsubstituted or singly or multiply substituted phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxanyl, pyridyl, pyrimidyl, pyrazinyl or benzothiophenyl; respectively unsubstituted or singly or multiply substituted phenyl, furyl or thiophenyl bound by a saturated, unbranched C1-2 alkyl group.
Particularly preferred are substituted cyclohexyl-1,4-diamine derivatives, wherein R3 represents respectively substituted or unsubstituted phenyl, thiophenyl, pyridyl or benzyl, particularly preferably 4-methylbenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-methylbenzyl, benzyl, phenyl, thiophenyl and 3-fluorophenyl.
Substituted cyclohexyl-1,4-diamine derivatives wherein n represents 2 or 3 are preferred.
Substituted cyclohexyl-1,4-diamine derivatives wherein R4 represents
—(CR6R7)pR8 and R5 represents H are also preferred.
Substituted cyclohexyl-1,4-diamine derivatives wherein R4 represents (CH2)pR8 and R5 represents —(CH2)lR8 are additionally preferred.
Substituted cyclohexyl-1,4-diamine derivatives wherein R4 and R5 together represent CH2CHR14OCHR14CH2, CH2CH2SCH2CH2, CH2CH2NR11CH2CH2 (CR12R13)3-6 or
Figure US08088763-20120103-C00005
are also preferred.
Substituted cyclohexyl-1,4-diamine derivatives wherein R6 represents H and R7 represents H, CH3, unsubstituted or singly or multiply substituted benzyl, or COOR9 or R6 and R7 form a ring (CH2)kCHR8(CH2)m are also preferred.
Substituted cyclohexyl-1,4-diamine derivatives wherein R8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl; respectively unsubstituted or singly or multiply substituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyrrolidinyl, tetrahydrofuryl, piperazinyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl are also preferred.
Substituted cyclohexyl-1,4-diamine derivatives wherein R8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl; respectively unsubstituted or singly or multiply substituted pyrrolidinyl, morpholinyl, tetrahydrofuryl, tetrahydronaphthyl, dihydroindolyl, pyridyl, thienyl, piperazinyl, naphthyl, indanyl, quinolinyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, furyl, benzofuryl, phenyl or indolyl are particularly preferred.
Most preferred are substituted cyclohexyl-1,4-diamine derivatives from the group comprising
  • N-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-oxo-tetrahydro-furan-3-yl)-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,3-diphenyl-propyl)-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(7-methoxy-benzo[1,3]dioxol-5-ylmethyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(3,6-dihydro-2H-pyridin-1-yl)-4-oxo-butyramide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-m-tolyl-piperazin-1-yl)-butyramide
  • 2-{3-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-propanoic acid ethylester
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-4-oxo-butyramide
  • 3-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-propanoic acid ethylester
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-methyl-N′-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-pyridin-2-yl-ethyl)-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-thiomorpholin-4-yl-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-thiophen-2-yl-ethyl)-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(4-ethoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-allyl-N′-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-methyl-succinamide
  • 5-[4-(2,5-dimethoxy-benzyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • 4-(3,6-dihydro-2H-pyridin-1-yl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4-oxo-butyramide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-pyridin-2-yl-piperazin-1-yl)-butyramide
  • ({3-[4-dimethylamino -4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-propionyl}-methyl-amino)-acetic acid benzyl ester
  • 4-[4-(2,6-dichloro-benzyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • {[4-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-butyryl]-methyl-amino}-acetic acid tert butyl ester
  • 5-[4-(2-fluoro-5-methoxy-benzyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-methoxy-propyl)-succinamide
  • 4-[4-(4-acetyl-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • 4-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionyl}-piperazin-1-carboxylic acid-tert-butylester
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(tetrahydro-furan-2-ylmethyl)-succinamide
  • 2-{3-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-propanoic acid ethylester
  • N-(3-bromo-benzyl)-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • 3-(4-chloro-phenyl)-2-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-propanoic acid methylester
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-naphthalen-1-ylmethyl-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-[4-(3-fluoro-4-methoxy-benzyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide
  • (4-{3-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-benzyl)-phosphonic acid diethylester
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-methyl-N′-(2-pyridin-2-yl-ethyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(3,6-dihydro-2H-pyridin-1-yl)-4-oxo-butyramide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)-succinamide
  • 5-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-chloro-6-methyl-benzyl)-succinamide
  • N-allyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-methyl-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-cyclopentyl-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(tetrahydro-furan-2-ylmethyl)-succinamide
  • (4-{3-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-benzyl)-phosphonic acid diethylester
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-[4-(3-methoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,5-difluoro-benzyl)-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-methyl-benzyl)-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-{4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidin-1-yl}-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide
  • 5-[4-(7-methoxy-benzo[1,3]dioxol-5-ylmethyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohex)/l)-amide
  • N-benzyl-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-(2-hydroxy-ethyl)-succinamide
  • 5-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-4-oxo-butyramide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4-oxobutyramide
  • 2-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-propanoic acid-tert-butylester
  • 5-(4-cycloheptyl-piperazin-1-yl)-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(4-fluoro-phenyl)-ethyl]-amide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-amide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-oxo-butyramide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-thiomorpholin-4-yl-butyramide
  • 4-(4-benzoyl-piperidin-1-yl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,4-dimethoxy-benzyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-ethyl-N′-pyridin-4-ylmethyl-succinamide
  • N-[2-(3,4-dimethoxy-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-methyl-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-methyl-N′-pyridin-3-ylmethyl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-pyridin-2-ylmethyl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-methyl-benzyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(4-methoxy-phenyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-indan-2-yl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)-succinamide
  • N-(2-chloro-6-methyl-benzyl)-N′-[4-dimethylamino -4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-[2-(4-fluoro-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide 4-dimethylamino-benzylamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,5-dichloro-benzyl)-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)-succinamide
  • 4-{3-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionyl}-piperazin-1-carboxylic acid ethylester
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(4-methoxy-benzyl)-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(2,6-dimethyl-morpholin-4-yl)-4-oxo-butyramide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide
  • 4-[4-(4-allyloxy-benzyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(5-bromo-2-methoxy-phenyl)-ethyl]-amide
  • 5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4-oxo-butyramide
  • (4-{3-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-benzyl)-phosphonic acid diethylester
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-o-tolyl-piperazin-1-yl)-butyramide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide
  • 4-[4-(4-chloro-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[1-(4-fluoro-phenyl)-ethyl]-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[1-(4-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-5-yl-succinamide
  • N-(4-benzyloxy-phenyl)-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide
  • 2-{3-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-3-methyl-valeric acid tert-butyl ester
  • 4-(4-benzyl-piperidin-1-yl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(1,2-dimethyl-propyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-4-oxo-butyramide
  • 4-[4-(3-chloro-benzoyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]cyclohexyl]-4-oxo-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(4-methoxy-phenyl)-succinamide
  • 5-[4-(2,6-dichloro-benzyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[1-(4-fluoro-phenyl)-ethyl]-succinamide
  • 4-[4-(4-chloro-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-(4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5]dec-8-yl)-butyramide
  • N-benzyl-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-methyl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,5-difluoro-benzyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(4-fluoro-phenyl)-ethyl]-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-succinamide
  • N-(2-benzylsulphanyl-ethyl)-N′-[4-dimethylamino -4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,4-difluoro-benzyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-phenethyl-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1-naphthalen-2-yl-ethyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-methoxymethyl-2-phenyl-ethyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,4-dichloro-benzyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-furan-2-ylmethyl-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(4-fluoro-benzyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-indan-1-yl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(3,5-dimethyl-piperidin-1-yl)-4-oxo-butyramide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-phenethyl-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-phenethyl-succinamide
  • N-(2-benzylsulphanyl-ethyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,5-dichloro-benzyl)-succinamide
  • 4-[4-(3-chloro-benzoyl)-piperazin-1-yl]-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-phenyl-propyl)-succinamide
  • N-(4-bromo-2-fluoro-benzyl)-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-methyl-N′-pyridin-3-ylmethyl-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(2-ethoxy-benzyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohhexyl]-N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-succinamide
  • N-(4-sec-butyl-phenyl)-N′-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • 5-oxo-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • 5-oxo-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide
  • N-(3-bromo-benzyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • N-(4-bromo-2-fluoro-benzyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-phenyl-propyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(4-fluoro-2-trifluoromethyl-benzyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-2-yl-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-butyramide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(2-fluoro-phenyl)-ethyl]-amide
  • N-[2-(2-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,4-difluoro-benzyl)-succinamide
  • N-benzyl-N-(2-cyano-ethyl)-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-methyl-benzyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(4-fluoro-3-trifluoromethyl-benzyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-chloro-phenyl)-ethyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(4-chloro-phenyl)-ethyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2,4-dichloro-phenyl)-ethyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-1-yl-succinamide
  • N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-1-yl-succinamide
  • N-[2-(4-chloro-phenyl)-propyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-(3-bromo-benzyl)-N′-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-phenyl-propyl)-succinamide
  • N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(2-p-tolyl-ethyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-thiophen-2-yl-ethyl)-succinamide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(4-chloro-phenyl)-propyl]-amide
  • N-benzyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-methyl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-chloro-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(2-ethoxy-phenyl)-ethyl]-amide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide phenethyl-amide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(3-chloro-phenyl)-ethyl]-amide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[1-(3-methoxy-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide (1,3-dimethyl-butyl)-amide
  • N-benzyl-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-ethyl-succinamide
  • N-(4-chloro-benzyl)-N′-[4-(3-chloro -benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-fluoro-benzyl)-succinamide
  • N-[2-(4-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[2-(2-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[2-(3-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-benzyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-(2-cyano-ethyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-chloro-4-fluoro-benzyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-trifluoromethyl-benzyl)-succinamide
  • N-[2-(2,4-dichloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-benzyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-ethyl-succinamide
  • N-[2-(4-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide
  • 5-oxo-5-(4-o-tolyl-piperazin-1-yl)-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[3-(methyl-phenyl-amino)-propyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-4-oxo-butyramide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(2-ethoxy-phenyl)-ethyl]-succinamide
  • 4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-butyramide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-ethoxy-phenyl)-ethyl]-succinamide
  • N-[2-(2,6-dichloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-benzhydryl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • N-[4-(3-chloro -benzyl)-4-dimethylamino-cyclohexyl]-N′-cyclooctyl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(4-phenoxy-phenyl)-ethyl]-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2,3-dimethyl-benzyl)-succinamide
  • 4-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • 4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-succinamide
  • N-(2-chloro-benzyl)-N′-[4-dimethylamino -4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-(2-chloro-benzyl)-N′-[4-(3 -chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-fluoro-5-trifluoromethyl-benzyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-p-tolyl-ethyl)-succinamide
  • N-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-trifluoromethyl-phenyl)-ethyl]-succinamide
  • N-[2-(3,4-dichloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(2-fluoro-phenyl)-piperazin-1-yl]-4-oxo-butyramide
  • 5-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cycloh
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-naphthalen-1-yl-ethyl)-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1-naphthalen-1 -yl-ethyl)-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-fluoro-benzyl)-N′-furan-2-ylmethyl-succinamide
  • N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-fluoro-benzyl)-N′-furan-2-ylmethyl-succinamide
  • N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,5-dimethoxy-benzyl)-N′-furan-2-ylmethyl-succinamide
  • N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-4-(2,3-dihydro-indol-1-yl)-4-oxo-butyramide
  • 4-(2,3-dihydro-indol-1-yl)-N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-4-oxo-butyramide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2-chloro-6-methyl-benzyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(3-methoxy-phenyl)-ethyl]-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3-methyl-benzyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(4-bromo-2-fluoro-benzyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-pyridin-4-ylmethyl-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-indan-1-yl-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2,4-dimethoxy-benzyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-thiophen-2-ylmethyl-succinamide
  • N-adamantan-1-ylmethyl-N′-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2,5-difluoro-benzyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(4-tert-butyl-phenyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3,5-bis-trifluoromethyl-benzyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(2-ethoxy-phenyl)-ethyl]-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3-methoxy-propyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2-morpholin-4-yl-ethyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2,5-dichloro-benzyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[1-(2-benzyloxy-benzyl)-pyrrolidin-3-yl]-N′-methyl-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-oxo-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-butyramide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-morpholin-4-yl-4-oxo-butyramide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3-dimethylamino-propyl)-N′-methyl-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2-phenyl-cyclopropyl)-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-naphthalen-1-ylmethyl-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-butyramide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-(4-hydroxy-piperidin-1-yl)-4-oxo-butyramide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(7-methyl-1H-indol-3-yl)-ethyl]-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-succinamide
  • N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-oxo-4-(4-quinolin-2-ylmethyl-piperazin-1-yl)-butyramide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-oxo-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-butyramide
  • Glutaric acid-(1-adamantan-1-yl-ethyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • N-[2-(2,6-dichloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide
  • N-(4-dimethylamino-4-thi thiophen-2-yl-cyclohexyl)-N′-(1-methyl-3-phenyl-propyl)-succinamide
  • N-benzyl-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N-ethyl-succinamide
  • N-[2 -(4-bromo-phenyl)-ethyl]-N′-(4-dimethylamino -4-thiophen-2-yl-cyclohexyl)-succinamide
  • 4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-oxo-butyramide
  • Glutaric acid-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3-phenyl-propyl)-amide
  • N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-pentyl-succinamide
  • 3-(4-chloro-phenyl)-2-[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyrylamino]-propanoic acid ethylester
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide indan-1-ylamide
  • N-adamantan-1-ylmethyl-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide
  • 5-(4-benzofuran-2-ylmethyl-piperazin-1-yl)-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • 4-[4-(4-tert-butyl-benzyl)-piperazin-1-yl]-N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-oxo-butyramide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(1H-indol-3-yl)-ethyl]-amide
  • N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-4-oxo-butyramide
  • 5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • 4-(4-benzyl-piperidin-1-yl)-N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-oxo-butyramide
  • {[4-(4-dimethylamino -4-thiophen-2-yl-cyclohexylcarbamoyl)-butyryl]-methyl-amino}-acetic acid benzylester
  • N-benzyl-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-N-phenethyl-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide 3-trifluoromethoxy-benzylamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide ethyl-(2-methyl-allyl)-amide
  • N,N-bis-(2-cyano-ethyl)-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide
  • Glutaric acid-benzyl-methyl-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(2-benzyloxy-cyclopentyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide 4-trifluoromethyl-benzylamide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(4-phenoxy-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3,3-diphenyl-propyl)-amide
  • 4-(4-benzyl-piperidin-1-yl)-N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-oxo-butyramide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-4-oxo-butyramide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide 4-fluoro-2-trifluoromethyl-benzylamide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-pentyl-succinamide
  • 5-[4-(2-methoxy-naphthalen-1-ylmethyl)-piperazin-1-yl]-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(2-ethoxy-benzyl)-N′-furan-2-ylmethyl-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2-phenyl-cyclopropyl)-amide
  • N-[2-(3,4-dichloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide
  • N-adamantan-1-ylmethyl-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide 5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • 2-[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyrylamino]-4-methyl-valeric acid benzyl ester
  • {4-[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyrylamino]-phenyl}-carbamic acid-tert-butylester
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(3-methoxy-phenyl)-ethyl]-amide
  • Glutaric acid-benzyl-ethyl-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-3-chloro-benzylamide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (4-methyl-cyclohexyl)-amide
  • N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide
  • Glutaric acid-2,5-dichloro-benzylamide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(3-fluoro-phenyl)-ethyl]-amide
  • N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(4-methoxy-phenoxy)-ethyl]-succinamide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(ethyl-m-tolyl-amino)-ethyl]-succinamide
  • Glutaric acid-(4-benzyloxy-phenyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(4-fluoro-phenyl)-ethyl]-amide
  • Glutaric acid-[2-(4-bromo-phenyl)-ethyl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(4-phenoxy-phenyl)-succinamide
  • N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(3-trifluoromethyl-phenyl)-ethyl]-succinamide
  • Glutaric acid-[2-(4-chloro-phenyl)-propyl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(4-methoxy-phenoxy)-ethyl]-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3-phenoxy-phenyl)-amide
  • N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(ethyl-m-tolyl-amino)-ethyl]-succinamide
  • Glutaric acid-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(3-trifluoromethyl-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (1-methyl-3-phenyl-propyl)-amide
  • N-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2,2-diphenyl-propyl)-amide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[3-(methyl-phenyl-amino)-propyl]-succinamide
  • N-(1-biphenyl-4-ylmethyl-pyrrolidin-3-yl)-N′-(4-dimethylamino -4-thiophen-2-yl-cyclohexyl)-N-methyl-succinamide
  • Glutaric acid-[4-(cyano-phenyl-methyl)-phenyl]-amide (4-dimethylamino-4-thiophen-2-ylcyclohexyl)-amide
  • Glutaric acid-(4-tert-butyl-cyclohexyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-sec-butyl-phenyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-butyl-phenyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • N-(2-benzylsulphanyl-ethyl)-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(2-phenoxy-ethyl)-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (naphthalen-1-ylmethyl)-amide
  • Glutaric acid-3-bromo-benzylamide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(3-phenyl-propyl)-succinamide
  • N-[2-(3-chloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide
  • 2-[3-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-propionylamino]-propanoic acid benzylester
  • N-[2-(2-chloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide
  • N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2-thiophen-2-yl-ethyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(4-phenoxy-phenyl)-ethyl]-amide
  • N-[2-(4-chloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide
  • N-[2-(3-chloro-phenyl)-ethyl]-N′-(4-dimethylamino -4-thiophen-2-yl-cyclohexyl)-succinamide
  • N-benzyl-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N-ethyl-succinamide
  • Glutaric acid-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3-phenyl-propyl)-amide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(1H-indol-3-yl)-ethyl]-amide
  • 5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide
  • {[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyryl]-methyl-amino}-acetic acid benzylester
  • N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(4-phenoxy-phenyl)-ethyl]-succinamide
  • Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2-phenyl-cyclopropyl)-amide
  • N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-ylmethylsuccinic acid amide hydrochloride, non-polar diastereoisomer
  • N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-ylmethylsuccinic acid amide hydrochloride, polar diastereoisomer
  • Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(2-fluorophenyl)ethyl]amide hydrochloride, non-polar diastereoisomer
  • Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(2-fluorophenyl)ethyl] amide hydrochloride, polar diastereoisomer
  • N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]-succinic acid amide hydrochloride, non-polar diastereoisomer
  • N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]-succinic acid amide hydrochloride, polar diastereoisomer
  • Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(4-chlorophenyl)ethyl]amide hydrochloride, non-polar diastereoisomer
in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
The substances according to the invention act, for example, on the ORL1 receptor that is relevant in connection with various diseases, so they are suitable as a pharmaceutical active ingredient in a pharmaceutical composition. The invention therefore further relates to pharmaceutical compositions containing at least one substituted cyclohexyl carboxylic acid derivative according to the invention, and optionally suitable additives and/or auxiliaries and/or optionally further active ingredients.
The pharmaceutical compositions according to the invention contain, in addition to at least one substituted cyclohexyl-1,4-diamine derivative according to the invention, optionally suitable additives and/or auxiliaries, therefore also excipients, fillers, solvents, diluents, dyes and/or binders and can be administered as liquid pharmaceutical compositions in the form of injection solutions, drops or syrups, as semi-solid pharmaceutical compositions in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of auxiliaries, etc. and the amounts thereof to be used depend on whether the pharmaceutical composition is to be applied orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes. Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral application, solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative applications. Substituted cyclohexyl-1,4-diamine derivatives according to the invention in a deposit, in dissolved form or in a plaster, optionally with the addition of agents to promote skin penetration, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the substituted cyclohexyl-1,4-diamine derivatives according to the invention after a delay. The substituted cyclohexyl-1,4-diamine derivatives according to the invention may also be applied in the form of parenteral long-acting repositories such as implants or implanted pumps. In principle, further active ingredients known to the person skilled in the art can be added to the pharmaceutical compositions according to the invention.
The amount of active ingredient to be administered to the patient varies as a function of the weight of the patient, the method of application, the indication and the severity of the illness. Conventionally, 0.00005 to 50 mg/kg, preferably 0.01 to 5 mg/kg, of at least one substituted cyclohexyl-1,4-diamine derivative according to the invention are applied.
For all of the above-mentioned forms of the pharmaceutical composition according to the invention, it is particularly preferred if, in addition to at least one substituted cyclohexyl-1,4-diamine derivative, the pharmaceutical composition contains a further active ingredient, in particular an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
In a preferred form of the pharmaceutical composition, a contained substituted cyclohexyl-1,4-diamine derivative according to the invention is in the form of a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
Both the ORL1 receptor and the further opioid receptors have been identified in particular in the occurrence of pain. Accordingly, substituted cyclohexyl-1,4-diamine derivatives according to the invention can be used for producing a pharmaceutical composition for the treatment of pain, in particular acute, neuropathic or chronic pain.
The invention therefore further relates to the use of a substituted cyclohexyl-1,4-diamine derivative according to the invention for producing a pharmaceutical composition for treating pain, in particular acute, visceral, neuropathic or chronic pain.
The invention further relates to the use of a substituted cyclohexyl-1,4-diamine derivative according to the invention for the production of a pharmaceutical composition for the treatment of anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, catalepsy, general cognitive dysfunction, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol- and/or drug- and/or medicine abuse and/or dependency, sexual dysfunction, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing difficulties, deficient intestine motility, impaired absorption of nutrients, anorexia, obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinence, or as a muscle relaxant, anti-convulsive or anaesthetic or for co-administration in treatment with an opioid analgesic or anaesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulation of motor activity, for modulation of neurotransmitter release and treatment of neurodegenerative diseases connected therewith, for the treatment of withdrawal symptoms and/or for reducing opioid addiction potential.
In this case it may be preferred in one of the present uses if a substituted cyclohexyl-1,4-diamine derivative used is in the form of a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
The invention further relates to a process for the treatment, in particular in one of the above-mentioned indications, of a non-human mammal or human, which or who requires treatment of pain, in particular chronic pain, by administration of a therapeutically effective dose of a substituted cyclohexyl-1,4-diamine derivative according to the invention, or of a pharmaceutical composition according to the invention.
The invention further relates to a process for producing the substituted cyclohexyl-1,4-diamine derivatives according to the invention, as stated in the following description and examples.
The radicals R01 and R02 have the meaning given for compounds according to the invention of formula I for R1 and R2 and, in addition, independently of one another can represent a protecting group. The remaining radicals have the meaning indicated in formula I:
Figure US08088763-20120103-C00006
Basically the various methods known to a person skilled in the art for producing amides are suitable for preparing the diamides according to the invention. The process according to the invention involves linking substituted cyclohexane-1,4-diamines (WO 02090317) via anhydrides, open-chain dicarboxylic acids or preferably the activated analogues thereof, in particular the acid halides thereof, with further primary or secondary amines and thus converting them into compounds according to the invention. Preferably anhydrides are initially opened with a cyclohexane-1,4-diamine or a primary or secondary amine to form the corresponding semi-amides, before being reacted in the second step to the diamide by a complementary primary or secondary amine or a cyclohexane-1,4-diamine in the presence of dehydrating agents. In the second step, in particular, it may be advantageous to activate the carboxylic acid function of the intermediate semi-amide before producing the diamide by conversion into a carboxylic acid equivalent (for example acid chloride or active ester). The reactions with anhydrides preferably take place in polar or non-polar aprotic solvents such as DMF, DMSO, diethyl ether, diisopropylether, THF, toluene, dichloromethane or acetonitrile at temperatures between −20 and +110° C., preferably between −10 and +40° C.
In the case of reactions with acid chlorides, polar or non-polar aprotic solvents, to which an organic or inorganic auxiliary base, preferably tertiary amines such as triethylamine, diisopropylethylamine or DMAP, has been added, are also used. In addition to amines of this type, pyridine, for example, is also suitable as a base and as a solvent. Preferably acid chlorides are reacted with amines at −10 and +40° C. in dichloromethane or chloroform in the presence of triethylamine or pyridine and optionally catalytic amounts of DMAP. For the reaction of the carboxylic acid function of an intermediate semi-amide with a further amine, the entire range of methods for producing amides known to a person skilled in the art is available. Organic or inorganic dehydrating agents such as a molecular sieve, magnesium sulphate, sulphuric acid or carbodiimides such as DCC or DIC, the latter optionally in the presence of HOBt (1-hydroxybenzotriazole), are advantageously used. These reactions are also preferably conducted in polar or non-polar aprotic solvents at temperatures between −20 and +110° C., preferably between −10 and +40° C. The protecting groups are optionally then cleaved.
EXAMPLES
Certain embodiments of the present invention may be further understood by reference to the following specific examples. These examples and the terminology used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.
The yields of compounds produced have not been optimised.
All temperatures are uncorrected.
The term “ether” denotes diethyl ether, “EE” ethyl acetate and “DCM” dichloromethane. The term “equivalent” denotes amount of substance equivalent, “mp.” melting point or melting range, “decomp.” decomposition, “RT” room temperature, “abs.” absolute (anhydrous), “rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol. %” volume percent, “m %” mass percent and “M” is a concentration in mol/l.
Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was used as the stationary phase for column chromatography.
Thin-layer chromatography tests were carried out using HPTLC chromatoplates, silica gel 60 F 254, from E. Merck, Darmstadt.
The mixing ratios of eluants for chromatographic tests are always given in volume/volume.
The compounds used in the following were either commercially available, or production thereof is known from the prior art or has been derived from the prior art in a manner obvious to a person skilled in the art.
General Directions:
0.1 mmol cyclohexane-1,4-diamine and 0.1 mmol diisopropylethylamine in THF were added dropwise to 0.1 mmol of the anhydride. The mixture was stirred for 12 h and 2 M HCl were then added to the reaction solution. The carboxylic acid derivative was obtained by extraction with 3×2 ml dichloromethane and removal of the solvent.
0.1 mmol of the corresponding amine (see Table 1) and 1 equivalent dilsopropylcarbodiimide and 1 equivalent 1-hydroxybenzotriazole were added to the resultant product. The mixture was stirred for 12 h and a 1 M sodium carbonate solution was then added. The product was obtained by extraction with 3×2 ml ethyl acetate/THF in each case and removal of the solvent.
Table 1 cites the carboxylic acids used for the last step for the examples.
TABLE 1
List of examples and diagrams of the amine used in the last
synthesis step.
Example Name of example compound
1
Figure US08088763-20120103-C00007
 		N-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]- N′-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-succinamide
2
Figure US08088763-20120103-C00008
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-oxo-tetrahydro-furan-3- yl)-succinamide
3
Figure US08088763-20120103-C00009
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3,3-diphenyl-propyl)- succinamide
4
Figure US08088763-20120103-C00010
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-[4-(7-methoxy- benzo[1,3]dioxol-5-ylmethyl)-piperazin-1- yl]-4-oxo-butyramide
5
Figure US08088763-20120103-C00011
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(3,6-dihydro-2H-pyridin-1- yl)-4-oxo-butyramide
6
Figure US08088763-20120103-C00012
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-4-(4-m-tolyl-piperazin-1- yl)-butyramide
7
Figure US08088763-20120103-C00013
 		2-{3-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexylcarbamoyl]-propionylamino}- propanoic acid ethylester
8
Figure US08088763-20120103-C00014
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(8-fluoro-1,3,4,5-tetrahydro- pyrido[4,3-b]indol-2-yl)-4-oxo-butyramide
9
Figure US08088763-20120103-C00015
 		3-{3-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexylcarbamoyl]-propionylamino}- propanoic acid ethylester
10
Figure US08088763-20120103-C00016
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-[4-(5-methyl-pyrazin-2- carbonyl)-piperazin-1-yl]-4-oxo-butyramide
11
Figure US08088763-20120103-C00017
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-methyl-N′-[2-(2,2,2-trifluoro- acetylamino)-ethyl]-succinamide
12
Figure US08088763-20120103-C00018
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-pyridin-2-yl-ethyl)- succinamide
13
Figure US08088763-20120103-C00019
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-oxo-4-thiomorpholin-4-yl- butyramide
14
Figure US08088763-20120103-C00020
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-[4-(5-methyl-pyrazin-2- carbonyl)-piperazin-1-yl]-4-oxo-butyramide
15
Figure US08088763-20120103-C00021
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(2-thiophen-2-yl-ethyl)- succinamide
16
Figure US08088763-20120103-C00022
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-[4-(4-ethoxy-phenyl)- piperazin-1-yl]-4-oxo-butyramide
17
Figure US08088763-20120103-C00023
 		N-allyl-N′-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-N-methyl- succinamide
18
Figure US08088763-20120103-C00024
 		5-[4-(2,5-dimethoxy-benzyl)-piperazin-1- yl]-5-oxo-valeric acid (4-benzyl-4- dimethylamino-cyclohexyl)-amide
19
Figure US08088763-20120103-C00025
 		4-(3,6-dihydro-2H-pyridin-1-yl)-N-[4- dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
20
Figure US08088763-20120103-C00026
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4- oxo-butyramide
21
Figure US08088763-20120103-C00027
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-4-(4-pyridin-2-yl- piperazin-1-yl)-butyramide
22
Figure US08088763-20120103-C00028
 		({3-[4-dimethylainino-4-(3-methyl-benzyl)- cyclohexylcarbamoyl]-propionyl}-methyl- amino)-acetic acid benzyl ester
23
Figure US08088763-20120103-C00029
 		4-[4-(2,6-dichloro-benzyl)-piperazin-1-yl]- N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
24
Figure US08088763-20120103-C00030
 		{[4-(4-benzyl-4-dimethylamino- cyclohexylcarbamoyl)-butyryl]-methyl- amino}-acetic acid tert butyl ester
25
Figure US08088763-20120103-C00031
 		5-[4-(2-fluoro-5-methoxy-benzyl)-piperazin- 1-yl]-5-oxo-valeric acid (4-benzyl-4- dimethylamino-cyclohexyl)-amide
26
Figure US08088763-20120103-C00032
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3-methoxy-propyl)- succinamide
27
Figure US08088763-20120103-C00033
 		4-[4-(4-Acetyl-phenyl)-piperazin-1-yl]-N-[4- dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
28
Figure US08088763-20120103-C00034
 		4-{3-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexylcarbamoyl]-propionyl}-piperazin- 1-carboxylic acid-tert-butylester
29
Figure US08088763-20120103-C00035
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(tetrahydro-furan-2- ylmethyl)-succinamide
30
Figure US08088763-20120103-C00036
 		2-{3-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexylcarbamoyl]-propionylamino}- propanoic acid ethylester
31
Figure US08088763-20120103-C00037
 		N-(3-bromo-benzyl)-N′-[4-dimethylamino-4- (3-methyl-benzyl)-cyclohexyl]-succinamide
32
Figure US08088763-20120103-C00038
 		3-(4-chloro-phenyl)-2-{3-[4-dimethylamino- 4-(4-methyl-benzyl)-cyclohexylcarbamoyl]- propionylamino}-propanoic acid methylester
33
Figure US08088763-20120103-C00039
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-[4-(5-methyl-pyrazin-2- carbonyl)-piperazin-1-yl]-4-oxo-butyramide
34
Figure US08088763-20120103-C00040
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-naphthalen-1-ylmethyl- succinamide
35
Figure US08088763-20120103-C00041
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-[4-(3-fluoro-4-methoxy- benzyl)-piperazin-1-yl]-4-oxo-butyramide
36
Figure US08088763-20120103-C00042
 		N-[4-dimethylamino-4-(4-methyl- benzyl)-cyclohexyl]-N′-[2-(1H-indol-3- yl)-ethyl]-N′-methyl-succinamide
37
Figure US08088763-20120103-C00043
 		(4-{3-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexylcarbamoyl]- propionylamino}-benzyl)-phosphonic acid diethylester
38
Figure US08088763-20120103-C00044
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-methyl-N′-(2-pyridin-2-yl- ethyl)-succinamide
39
Figure US08088763-20120103-C00045
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(3,6-dihydro-2H-pyridin-1- yl)-4-oxo-butyramide
40
Figure US08088763-20120103-C00046
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)- succinamide
41
Figure US08088763-20120103-C00047
 		5-[4-(5-methyl-pyrazin-2-carbonyl)- piperazin-1-yl]-5-oxo-valeric acid (4-benzyl- 4-dimethylamino-cyclohexyl)-amide
42
Figure US08088763-20120103-C00048
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-chloro-6-methyl-benzyl)- succinamide
43
Figure US08088763-20120103-C00049
 		N-allyl-N′-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-N-methyl- succinamide
44
Figure US08088763-20120103-C00050
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-Nt-cyclopentyl-succinamide
45
Figure US08088763-20120103-C00051
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-(tetrahydro-furan-2- ylmethyl)-succinamide
46
Figure US08088763-20120103-C00052
 		(4-{3-[4-dimethylamino-4-(3-methyl- benzyl)-cyclohexylcarbamoyl]- propionylamino}-benzyl)-phosphonic acid diethylester
47
Figure US08088763-20120103-C00053
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-[4-(2-methoxy-phenyl)- piperazin-1-yl]-4-oxo-butyramide
48
Figure US08088763-20120103-C00054
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-[4-(3-methoxy-phenyl)- piperazin-1-yl]-4-oxo-butyramide
49
Figure US08088763-20120103-C00055
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3,5-difluoro-benzyl)- succinamide
50
Figure US08088763-20120103-C00056
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-methyl-benzyl)- succinamide
51
Figure US08088763-20120103-C00057
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-4-{4-[(2,2,2-trifluoro- acetylamino)-methyl]-piperidin-1-yl}- butyramide
52
Figure US08088763-20120103-C00058
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]- succinamide
53
Figure US08088763-20120103-C00059
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′- methyl-succinamide
54
Figure US08088763-20120103-C00060
 		5-[4-(7-methoxy-benzo[1,3]dioxol-5- ylmethyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohex)/1)- amide
55
Figure US08088763-20120103-C00061
 		N-benzyl-N′-[4-dimethylamino-4-(3-methyl- benzyl)-cyclohexyl]-N-(2-hydroxy-ethyl)- succinamide
56
Figure US08088763-20120103-C00062
 		5-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]- 5-oxo-valeric acid (4-benzyl-4- dimethylamino-cyclohexyl)-amide
57
Figure US08088763-20120103-C00063
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′- methyl-succinamide
58
Figure US08088763-20120103-C00064
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-[4-(2,3-dimethyl-phenyl)- piperazin-1- yl]-4-oxo-butyramide
59
Figure US08088763-20120103-C00065
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide (1,2,3,4-tetrahydro- naphthalen-1-yl)-amide
60
Figure US08088763-20120103-C00066
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4- oxobutyramide
61
Figure US08088763-20120103-C00067
 		2-{3-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexylcarbamoyl]-propionylamino}- propanoic acid-tert-butylester
62
Figure US08088763-20120103-C00068
 		5-(4-cycloheptyl-piperazin-1-yl)-5-oxo- valeric acid (4-benzyl-4-dimethylamino- cyclohexyl)-amide
63
Figure US08088763-20120103-C00069
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide[2-(4-fluoro-phenyl)- ethyl]-amide
64
Figure US08088763-20120103-C00070
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide[1-(2,6-dichloro-benzyl)- pyrrolidin-3-yl]-amide
65
Figure US08088763-20120103-C00071
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(1,4-dioxa-8-aza- spiro[4.5]dec-8-yl)-4-oxo-butyramide
66
Figure US08088763-20120103-C00072
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-oxo-4-thiomorpholin-4-yl- butyramide
67
Figure US08088763-20120103-C00073
 		4-(4-benzoyl-piperidin-1-yl)-N-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
68
Figure US08088763-20120103-C00074
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2,4-dimethoxy-benzyl)- succinamide
69
Figure US08088763-20120103-C00075
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(1,2,3,4-tetrahydro- naphthalen-1-yl)-succinamide
70
Figure US08088763-20120103-C00076
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-ethyl-N′-pyridin-4-ylmethyl- succinamide
71
Figure US08088763-20120103-C00077
 		N-[2-(3,4-dimethoxy-phenyl)-ethyl]-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N-methyl-succinamide
72
Figure US08088763-20120103-C00078
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-methyl-N′-pyridin-3- ylmethyl-succinamide
73
Figure US08088763-20120103-C00079
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-pyridin-2-ylmethyl- succinamide
74
Figure US08088763-20120103-C00080
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-methyl-benzyl)- succinamide
75
Figure US08088763-20120103-C00081
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(4-methoxy-phenyl)- succinamide
76
Figure US08088763-20120103-C00082
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-indan-2-yl-succinamide
77
Figure US08088763-20120103-C00083
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)- succinamide
78
Figure US08088763-20120103-C00084
 		N-(2-chloro-6-methyl-benzyl)-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
79
Figure US08088763-20120103-C00085
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-[4-(4-methoxy-phenyl)- piperazin-1-yl]-4-oxo-butyramide
80
Figure US08088763-20120103-C00086
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-[2-(4-fluoro-phenyl)-ethyl]- succinamide
81
Figure US08088763-20120103-C00087
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide 4-dimethylamino- benzylamide
82
Figure US08088763-20120103-C00088
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3,5-dichloro-benzyl)- succinamide
83
Figure US08088763-20120103-C00089
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)- succinamide
84
Figure US08088763-20120103-C00090
 		4-{3-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexylcarbamoyl]-propionyl}-piperazin- 1-carboxylic acid ethylester
85
Figure US08088763-20120103-C00091
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(4-methoxy-benzyl)- succinamide
86
Figure US08088763-20120103-C00092
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(2,6-dimethyl-morpholin-4- yl)-4-oxo-butyramide
87
Figure US08088763-20120103-C00093
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-4-(4-phenyl-3,6-dihydro- 2H-pyridin-1-yl)-butyramide
88
Figure US08088763-20120103-C00094
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]- succinamide
89
Figure US08088763-20120103-C00095
 		4-[4-(4-allyloxy-benzyl)-piperazin-1-yl]-N- [4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
90
Figure US08088763-20120103-C00096
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide[2-(5-bromo-2-methoxy- phenyl)-ethyl]-amide
91
Figure US08088763-20120103-C00097
 		5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5- oxo-valeric acid (4-benzyl-4-dimethylamino- cyclohexyl)-amide
92
Figure US08088763-20120103-C00098
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4- oxo-butyramide
93
Figure US08088763-20120103-C00099
 		(4-{3-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexylcarbamoyl]- propionylamino}-benzyl)-phosphonic acid diethylester
94
Figure US08088763-20120103-C00100
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-4-(4-o-tolyl-piperazin-1- yl)-butyramide
95
Figure US08088763-20120103-C00101
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]- succinamide
96
Figure US08088763-20120103-C00102
 		4-[4-(4-chloro-phenyl)-piperazin-1-yl]-N-[4- dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
97
Figure US08088763-20120103-C00103
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[1-(4-fluoro-phenyl)-ethyl]- succinamide
98
Figure US08088763-20120103-C00104
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[1-(4-trifluoromethyl- benzyl)-pyrrolidin-3-yl]-succinamide
99
Figure US08088763-20120103-C00105
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]- succinamicle
100
Figure US08088763-20120103-C00106
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-indan-5-yl-succinamide
101
Figure US08088763-20120103-C00107
 		N-(4-benzyloxy-phenyl)-N′-[4- dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-succinamide
102
Figure US08088763-20120103-C00108
 		2-{3-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexylcarbamoyl]-propionylamino}-3- methyl-valeric acid tert-butyl ester
103
Figure US08088763-20120103-C00109
 		4-(4-benzyl-piperidin-1-yl)-N-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
104
Figure US08088763-20120103-C00110
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-[4-(4-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-4-oxo-butyramide
105
Figure US08088763-20120103-C00111
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-(1,2-dimethyl-propyl)- succinamide
106
Figure US08088763-20120103-C00112
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-(8-fluoro-1,3,4,5-tetrahydro- pyrido[4,3-b]indol-2-yl)-4-oxo-butyramide
107
Figure US08088763-20120103-C00113
 		4-[4-(3-chloro-benzoyl)-piperazin-1-yl]-N- [4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
108
Figure US08088763-20120103-C00114
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(4-methoxy-phenyl)- succinamide
110
Figure US08088763-20120103-C00115
 		5-[4-(2,6-dichloro-benzyl)-piperazin-1-yl]-5- oxo-valeric acid (4-benzyl-4-dimethylamino- cyclohexyl)-amide
111
Figure US08088763-20120103-C00116
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′- methyl-succinamide
112
Figure US08088763-20120103-C00117
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-[1-(4-fluoro-phenyl)-ethyl]- succinamide
113
Figure US08088763-20120103-C00118
 		4-[4-(4-chloro-phenyl)-piperazin-1-yl]-N-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
114
Figure US08088763-20120103-C00119
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-oxo-4-(4-oxo-1-phenyl-1,3,8- triaza-spiro[4.5]dec-8-yl)-butyramide
115
Figure US08088763-20120103-C00120
 		N-benzyl-N′-[4-dimethylamino-4-(3-methyl- benzyl)-cyclohexyl]-N-methyl-succinamide
116
Figure US08088763-20120103-C00121
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3,5-difluoro-benzyl)- succinamide
117
Figure US08088763-20120103-C00122
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-[2-(4-fluoro-phenyl)-ethyl]- succinamide
118
Figure US08088763-20120103-C00123
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]- succinamide
119
Figure US08088763-20120103-C00124
 		N-(2-benzylsulphanyl-ethyl)-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
120
Figure US08088763-20120103-C00125
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2,4-difluoro-benzyl)- succinamide
121
Figure US08088763-20120103-C00126
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-phenethyl-succinamide
122
Figure US08088763-20120103-C00127
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(1-naphthalen-2-yl-ethyl)- succinamide
123
Figure US08088763-20120103-C00128
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1-methoxymethyl-2-phenyl- ethyl)-succinamide
124
Figure US08088763-20120103-C00129
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3,4-dichloro-benzyl)- succinamide
125
Figure US08088763-20120103-C00130
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-furan-2-ylmethyl- succinamide
126
Figure US08088763-20120103-C00131
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-(1,2,3,4-tetrahydro- naphthalen-1-yl)-succinamide
127
Figure US08088763-20120103-C00132
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(4-fluoro-benzyl)- succinamide
128
Figure US08088763-20120103-C00133
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-indan-1-yl-succinamide
129
Figure US08088763-20120103-C00134
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-(3,5-dimethyl-piperidin-1-yl)- 4-oxo-butyramide
130
Figure US08088763-20120103-C00135
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-phenethyl-succinamide
131
Figure US08088763-20120103-C00136
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-phenethyl-succinamide
132
Figure US08088763-20120103-C00137
 		N-(2-benzylsulphanyl-ethyl)-N′-[4-(3- chloro-benzyl)-4-dimethylamino- cyclohexyl]-succinamide
133
Figure US08088763-20120103-C00138
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2,5-dichloro-benzyl)- succinamide
134
Figure US08088763-20120103-C00139
 		4-[4-(3-chloro-benzoyl)-piperazin-1-yl]-N- [4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-oxo-butyramide
135
Figure US08088763-20120103-C00140
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1-phenyl-propyl)- succinamide
136
Figure US08088763-20120103-C00141
 		N-(4-bromo-2-fluoro-benzyl)-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
137
Figure US08088763-20120103-C00142
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-methyl- N′-pyridin-3-ylmethyl- succinamide
138
Figure US08088763-20120103-C00143
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-(2-ethoxy-benzyl)- succinamide
139
Figure US08088763-20120103-C00144
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(2-(5-methoxy-1H-indol-3- yl)-ethyl]-succinamide
140
Figure US08088763-20120103-C00145
 		N-(4-sec-butyl-phenyl)-N′-[4-(4-chloro- benzyl)-4-dimethylamino-cyclohexyl]- succinamide
141
Figure US08088763-20120103-C00146
 		5-oxo-5-(4-phenyl-3,6-dihydro-2H-pyridin- 1-yl)-valeric acid (4-benzyl-4- dimethylamino-cyclohexyl)-amide
142
Figure US08088763-20120103-C00147
 		5-oxo-5-(4-phenyl-3,6-dihydro-2H-pyridin- 1-yl)-valeric acid (4-benzyl-4- dimethylamino-cyclohexyl)-amide
143
Figure US08088763-20120103-C00148
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]- succinamide
144
Figure US08088763-20120103-C00149
 		N-(3-bromo-benzyl)-N′-[4-(3-chloro- benzyl)-4-dimethylamino-cyclohexyl]- succinamide
145
Figure US08088763-20120103-C00150
 		N-(4-bromo-2-fluoro-benzyl)-N′-[4-(3- chloro-benzyl)-4-dimethylamino- cyclohexyl]-succinamide
146
Figure US08088763-20120103-C00151
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1-phenyl-propyl)- succinamide
147
Figure US08088763-20120103-C00152
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(4-fluoro-2-trifluoromethyl- benzyl)-succinamide
148
Figure US08088763-20120103-C00153
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-indan-2-yl-succinamide
149
Figure US08088763-20120103-C00154
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-4-(4-phenyl-3,6-dihydro- 2H-pyridin-1-yl)-butyramide
150
Figure US08088763-20120103-C00155
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]- succinamide
151
Figure US08088763-20120103-C00156
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]- succinamide
152
Figure US08088763-20120103-C00157
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide[2-(2-fluoro-phenyl)- ethyl]-amide
153
Figure US08088763-20120103-C00158
 		N-[2-(2-chloro-phenyl)-ethyl]-N′-[4- dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-succinamide
154
Figure US08088763-20120103-C00159
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3,4-difluoro-benzyl)- succinamide
155
Figure US08088763-20120103-C00160
 		N-benzyl-N-(2-cyano-ethyl)-N′-[4- dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-succinamide
156
Figure US08088763-20120103-C00161
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3-methyl-benzyl)- succinamide
157
Figure US08088763-20120103-C00162
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(4-fluoro-3-trifluoromethyl- benzyl)-succinamide
159
Figure US08088763-20120103-C00163
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(2-chloro-phenyl)-ethyl]- succinamide
160
Figure US08088763-20120103-C00164
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(4-chloro-phenyl)-ethyl]- succinamide
161
Figure US08088763-20120103-C00165
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(2,4-dichloro-phenyl)- ethyl]-succinamide
162
Figure US08088763-20120103-C00166
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-indan-1-yl-succinamide
163
Figure US08088763-20120103-C00167
 		N-[4-(4-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-indan-1-yl-succinamide
164
Figure US08088763-20120103-C00168
 		N-[2-(4-chloro-phenyl)-propyl]-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
165
Figure US08088763-20120103-C00169
 		N-(3-bromo-benzyl)-N′-[4-(4-chloro- benzyl)-4-dimethylamino-cyclohexyl]- succinamide
167
Figure US08088763-20120103-C00170
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3-phenyl-propyl)- succinamide
168
Figure US08088763-20120103-C00171
 		N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-N′-(2-p-tolyl-ethyl)-succinamide
169
Figure US08088763-20120103-C00172
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-thiophen-2-yl-ethyl)- succinamide
170
Figure US08088763-20120103-C00173
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide[2-(4-chloro-phenyl)- propyl]-amide
171
Figure US08088763-20120103-C00174
 		N-benzyl-N′-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-N-methyl- succinamide
172
Figure US08088763-20120103-C00175
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(3-chloro-phenyl)-ethyl]- succinamide
173
Figure US08088763-20120103-C00176
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide[2-(2-ethoxy-phenyl)- ethyl]-amide
174
Figure US08088763-20120103-C00177
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide phenethyl-amide
175
Figure US08088763-20120103-C00178
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide[2-(3-chloro-phenyl)- ethyl]-amide
176
Figure US08088763-20120103-C00179
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[1-(3-methoxy-phenyl)- ethyl]-succinamide
177
Figure US08088763-20120103-C00180
 		Glutaric acid-(4-benzyl-4-dimethylamino- cyclohexyl)-amide (1,3-dimethyl-butyl)- amide
178
Figure US08088763-20120103-C00181
 		N-benzyl-N′-[4-dimethylamino-4-(3-methyl- benzyl)-cyclohexyl]-N-ethyl-succinamide
179
Figure US08088763-20120103-C00182
 		N-(4-chloro-benzyl)-N′-[4-(3-chloro- benzyl)-4-dimethylamino-cyclohexyl]- succinamide
180
Figure US08088763-20120103-C00183
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]- succinamide
181
Figure US08088763-20120103-C00184
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(2-fluoro-benzyl)- succinamide
182
Figure US08088763-20120103-C00185
 		N-[2-(4-chloro-phenyl)-ethyll-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
183
Figure US08088763-20120103-C00186
 		N-[2-(2-chloro-phenyl)-ethyl]-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
184
Figure US08088763-20120103-C00187
 		N-[2-(3-chloro-phenyl)-ethyl]-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
185
Figure US08088763-20120103-C00188
 		N-benzyl-N′-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-N-(2-cyano- ethyl)-succinamide
186
Figure US08088763-20120103-C00189
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3-chloro-4-fluoro-benzyl)- succinamide
187
Figure US08088763-20120103-C00190
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(2-trifluoromethyl-benzyl)- succinamide
188
Figure US08088763-20120103-C00191
 		N-[2-(2,4-dichloro-phenyl)-ethyl]-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
189
Figure US08088763-20120103-C00192
 		N-benzyl-N′-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-N-ethyl- succinamide
190
Figure US08088763-20120103-C00193
 		N-[2-(4-chloro-phenyl)-ethyl]-N′-[4- dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-succinamide
191
Figure US08088763-20120103-C00194
 		5-oxo-5-(4-o-tolyl-piperazin-1-yl)-valeric acid (4-benzyl-4-dimethylamino- cyclohexyl)-amide
192
Figure US08088763-20120103-C00195
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[3-(methyl-phenyl-amino)- propyl]-succinamide
193
Figure US08088763-20120103-C00196
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-[4-(5-chloro-2-methyl- phenyl)-piperazin-1-yl]-4-oxo-butyramide
194
Figure US08088763-20120103-C00197
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-[2-(2-ethoxy-phenyl)-ethyl]- succinamide
195
Figure US08088763-20120103-C00198
 		4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N- [4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-oxo-butyramide
196
Figure US08088763-20120103-C00199
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(2-ethoxy-phenyl)-ethyl]- succinamide
197
Figure US08088763-20120103-C00200
 		N-[2-(2,6-dichloro-phenyl)-ethyl]-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
198
Figure US08088763-20120103-C00201
 		N-benzhydryl-N′-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-succinamide
199
Figure US08088763-20120103-C00202
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-cyclooctyl-succinamide
200
Figure US08088763-20120103-C00203
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(4-phenoxy-phenyl)- ethyl]-succinamide
201
Figure US08088763-20120103-C00204
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(2,3-dimethyl-benzyl)- succinamide
202
Figure US08088763-20120103-C00205
 		4-[4-(5-chloro-2-methyl-phenyl)-piperazin- 1-yl]-N-[4-dimethylamino-4-(3-methyl- benzyl)-cyclohexyl]-4-oxo-butyramide
203
Figure US08088763-20120103-C00206
 		4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N- [4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-4-oxo-butyramide
204
Figure US08088763-20120103-C00207
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1,2,3,4-tetrahydro- naphthalen-1-yl)-succinamide
205
Figure US08088763-20120103-C00208
 		N-(2-chloro-benzyl)-N′-[4-dimethylamino-4- (3-methyl-benzyl)-cyclohexyl]-succinamide
206
Figure US08088763-20120103-C00209
 		N-(2-chloro-benzyl)-N′-[4-(3-chloro- benzyl)-4-dimethylamino-cyclohexyl]- succinamide
207
Figure US08088763-20120103-C00210
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(3-fluoro-5-trifluoromethyl- benzyl)-succinamide
208
Figure US08088763-20120103-C00211
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1-p-tolyl-ethyl)-succinamide
209
Figure US08088763-20120103-C00212
 		N-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]- N′-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-succinamide
210
Figure US08088763-20120103-C00213
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(2,6-dichloro- benzylsulphanyl)-ethyl]-succinamide
211
Figure US08088763-20120103-C00214
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-[2-(3-trifluoromethyl- phenyl)-ethyl]-succinamide
212
Figure US08088763-20120103-C00215
 		N-[2-(3,4-dichloro-phenyl)-ethyl]-N′-[4- dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-succinamide
213
Figure US08088763-20120103-C00216
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-4-[4-(2-fluoro-phenyl)- piperazin-1-yl]-4-oxo-butyramide
214
Figure US08088763-20120103-C00217
 		5-[4-(2,4-dimethoxy-phenyl)-piperazin-1- yl]-5-oxo-valeric acid (4-benzyl-4- dimethylamino-cyclohexyl)-amide
215
Figure US08088763-20120103-C00218
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(1-naplithalen-1-yl-ethyl)- succinamide
216
Figure US08088763-20120103-C00219
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(1-naplithalen-1-yl-ethyl)- succinamide
217
Figure US08088763-20120103-C00220
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2-fluoro-benzyl)-N′-furan-2- ylmethyl-succinamide
218
Figure US08088763-20120103-C00221
 		N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-N′-(2-fluoro-benzyl)-N′-furan-2- ylmethyl-succinamide
219
Figure US08088763-20120103-C00222
 		N-[4-(3-chloro-benzyl)-4-dimethylamino- cyclohexyl]-N′-(2,5-dimethoxy-benzyl)-N′- furan-2-ylmethyl-succinamide
220
Figure US08088763-20120103-C00223
 		N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-4- (2,3-dihydro-indol-1-yl)-4-oxo-butyramide
221
Figure US08088763-20120103-C00224
 		4-(2, 3-dihydro-indol-1-yl)-N-[4- dimethylamino-4-(3-fluoro-phenyl)- cyclohexyl]-4-oxo-butyramide
222
Figure US08088763-20120103-C00225
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(2-chloro-6-methyl-benzyl)-succinamide
223
Figure US08088763-20120103-C00226
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-[2-(3-methoxy-phenyl)-ethyl]- succinamide
224
Figure US08088763-20120103-C00227
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(3-methyl-benzyl)-succinamide
225
Figure US08088763-20120103-C00228
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(4-bromo-2-fluoro-benzyl)-succinamide
226
Figure US08088763-20120103-C00229
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-pyridin-4-ylmethyl-succinamide
227
Figure US08088763-20120103-C00230
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-indan-1-yl-succinamide
228
Figure US08088763-20120103-C00231
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(2,4-dimethoxy-benzyl)-succinamide
229
Figure US08088763-20120103-C00232
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-thiophen-2-ylmethyl-succinamide
230
Figure US08088763-20120103-C00233
 		N-adamantan-1-ylmethyl-N′-(4-benzyl-4- morpholin-4-yl-cyclohexyl)-succinamide
231
Figure US08088763-20120103-C00234
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(2,5-difluoro-benzyl)-succinamide
232
Figure US08088763-20120103-C00235
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(4-tert-butyl-phenyl)-succinamide
233
Figure US08088763-20120103-C00236
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(3,5-bis-trifluoromethyl-benzyl)- succinamide
234
Figure US08088763-20120103-C00237
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-[2-(2-ethoxy-phenyl)-ethyl]-succinamide
235
Figure US08088763-20120103-C00238
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(3-methoxy-propyl)-succinamide
236
Figure US08088763-20120103-C00239
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(2-morpholin-4-yl-ethyl)-succinamide
237
Figure US08088763-20120103-C00240
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(2,5-dichloro-benzyl)-succinamide
238
Figure US08088763-20120103-C00241
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-[1-(2-benzyloxy-benzyl)-pyrrolidin-3-yl]- N′-methyl-succinamide
239
Figure US08088763-20120103-C00242
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- 4-oxo-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin- 1-yl)-butyramide
240
Figure US08088763-20120103-C00243
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- 4-morpholin-4-yl-4-oxo-butyramide
241
Figure US08088763-20120103-C00244
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(3-dimethylamino-propyl)-N′-methyl- succinamide
242
Figure US08088763-20120103-C00245
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-(2-phenyl-cyclopropyl)-succinamide
243
Figure US08088763-20120103-C00246
 		N-(4-benzyl-4-morpholrn-4-yl-cyclohexyl)- N′-naphthalen-1-ylmethyl-succinamide
244
Figure US08088763-20120103-C00247
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- 4-(4-methyl-[1,4]diazepan-1-yl)-4-oxo- butyramide
245
Figure US08088763-20120103-C00248
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- 4-(4-hydroxy-piperidin-1-yl)-4-oxo- butyramide
246
Figure US08088763-20120103-C00249
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-[2-(7-methyl-1H-indol-3-yl)-ethyl]- succinamide
247
Figure US08088763-20120103-C00250
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]- succinamide
248
Figure US08088763-20120103-C00251
 		N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)- 4-oxo-4-(4-quinolin-2-ylmethyl-piperazin-1- yl)-butyramide
249
Figure US08088763-20120103-C00252
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-4-oxo-4-[4-(5-trifluoromethyl- pyndrn-2-yl)-piperazin-1-yl]-butyramide
250
Figure US08088763-20120103-C00253
 		Glutaric acid-(1-adamantan-1-yl-ethyl)- amide (4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-amide
251
Figure US08088763-20120103-C00254
 		N-[2-(2,6-dichloro-phenyl)-ethyl]-N′-(4- dimethylainino-4-thiophen-2-yl-cyclohexyl)- succinamide
252
Figure US08088763-20120103-C00255
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-(1-methyl-3-phenyl-propyl)- succinamide
253
Figure US08088763-20120103-C00256
 		N-benzyl-N′-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-N-ethyl-succinamide
254
Figure US08088763-20120103-C00257
 		N-[2-(4-bromo-phenyl)-ethyl]-N′-(4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- succinamide
255
Figure US08088763-20120103-C00258
 		4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N- (4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-4-oxo-butyramide
256
Figure US08088763-20120103-C00259
 		Glutaric acid-[1-(2,6-dichloro-benzyl)- pyrrolidin-3-yl]-amide (4-dimethylamino-4- thiophen-2-yl-cyclohexyl)-amide
257
Figure US08088763-20120103-C00260
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (3-phenyl-propyl)- amide
258
Figure US08088763-20120103-C00261
 		N-(4-dimethylamino-4-phenyl-cyclohexyl)- N′-pentyl-succinamide
259
Figure US08088763-20120103-C00262
 		3-(4-chloro-phenyl)-2-[4-(4-dimethylamino- 4-thiophen-2-yl-cyclohexylcarbamoyl)- butyrylamino]-propanoic acid ethylester
260
Figure US08088763-20120103-C00263
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide indan-1-ylamide
261
Figure US08088763-20120103-C00264
 		N-adamantan-1-ylmethyl-N′-(4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- succinamide
262
Figure US08088763-20120103-C00265
 		5-(4-benzofuran-2-ylmethyl-piperazin-1-yl)- 5-oxo-valeric acid (4-dimethylamino-4- thiophen-2-yl-cyclohexyl)-amide
263
Figure US08088763-20120103-C00266
 		4-[4-(4-tert-butyl-benzyl)-piperazin-1-yl]-N- (4-dimethylamino-4-phenyl-cyclohexyl)-4- oxo-butyramide
264
Figure US08088763-20120103-C00267
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide[2-(1H-indol-3-yl)- ethyl]-amide
265
Figure US08088763-20120103-C00268
 		N-(4-dimethylamino-4-phenyl-cyclohexyl)- 4-[4-hydroxy-4-(3-trifluoromethyl-phenyl)- piperidin-1-yl]-4-oxo-butyramide
266
Figure US08088763-20120103-C00269
 		5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxo- valeric acid (4-dimethylamino-4-thiophen-2- yl-cyclohexyl)-amide
267
Figure US08088763-20120103-C00270
 		4-(4-benzyl-piperidin-1-yl)-N-(4- dimethylamino-4-phenyl-cyclohexyl)-4-oxo- butyramide
268
Figure US08088763-20120103-C00271
 		{[4-(4-dimethylamino-4-thiophen-2-yl- cyclohexylcarbamoyl)-butyryl]-methyl- amino}-acetic acid benzylester
269
Figure US08088763-20120103-C00272
 		N-benzyl-N′-(4-dimethylamino-4-phenyl- cyclohexyl)-N-phenethyl-succinamide
270
Figure US08088763-20120103-C00273
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide 3-trifluoromethoxy- benzylamide
271
Figure US08088763-20120103-C00274
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide ethyl-(2-methyl- allyl)-amide
272
Figure US08088763-20120103-C00275
 		N,N-bis-(2-cyano-ethyl)-N′-(4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- succinamide
273
Figure US08088763-20120103-C00276
 		Glutaric acid-benzyl-methyl-amide (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
274
Figure US08088763-20120103-C00277
 		Glutaric acid-(2-benzyloxy-cyclopentyl)- amide (4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-amide
275
Figure US08088763-20120103-C00278
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide 4-trifluoromethyl- benzylamide
276
Figure US08088763-20120103-C00279
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-[2-(4-phenoxy-phenyl)- ethyl]-succinamide
277
Figure US08088763-20120103-C00280
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (3,3-diphenyl- propyl)-amide
278
Figure US08088763-20120103-C00281
 		4-(4-benzyl-piperidin-1-yl)-N-(4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- 4-oxo-butyramide
279
Figure US08088763-20120103-C00282
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-4-[4-hydroxy-4-(3- trifluoromethyl-phenyl)-piperidin-1-yl]-4- oxo-butyramide
280
Figure US08088763-20120103-C00283
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide 4-fluoro-2- trifluoromethyl-benzylamide
281
Figure US08088763-20120103-C00284
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-pentyl-succinamide
282
Figure US08088763-20120103-C00285
 		5-[4-(2-methoxy-naphthalen-1-ylmethyl)- piperazin-1-yl]-5-oxo-valeric acid (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
283
Figure US08088763-20120103-C00286
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-(2-ethoxy-benzyl)-N′-furan- 2-ylmethyl-succinamide
284
Figure US08088763-20120103-C00287
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (2-phenyl- cyclopropyl)-amide
285
Figure US08088763-20120103-C00288
 		N-[2-(3,4-dichloro-phenyl)-ethyl]-N′-(4- dimethylamino-4-phenyl-cyclohexyl)- succinamide
286
Figure US08088763-20120103-C00289
 		N-adamantan-1-ylmethyl-N′-(4- dimethylamino-4-phenyl-cyclohexyl)- succinamide
287
Figure US08088763-20120103-C00290
 		5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-5-oxo-valeric acid (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
288
Figure US08088763-20120103-C00291
 		2-[4-(4-dimethylamino-4-thiophen-2-yl- cyclohexylcarbamoyl)-butyrylamino]-4- methyl-valeric acid benzyl ester
289
Figure US08088763-20120103-C00292
 		{4-[4-(4-dimethylamino-4-thiophen-2-yl- cyclohexylcarbamoyl)-butyrylamino]- phenyl}-carbamic acid-tert-butylester
290
Figure US08088763-20120103-C00293
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide[2-(3-methoxy- phenyl)-ethyl]-amide
291
Figure US08088763-20120103-C00294
 		Glutaric acid-benzyl-ethyl-amide (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
292
Figure US08088763-20120103-C00295
 		Glutaric acid-3-chloro-benzylamide (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
293
Figure US08088763-20120103-C00296
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (4-methyl- cyclohexyl)-amide
294
Figure US08088763-20120103-C00297
 		N-(4-dimethylamino-4-phenyl-cyclohexyl)- N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl- succinamide
295
Figure US08088763-20120103-C00298
 		Glutaric acid-2,5-dichloro-benzylamide (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
296
Figure US08088763-20120103-C00299
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide[2-(3-fluoro- phenyl)-ethyl]-amide
297
Figure US08088763-20120103-C00300
 		N-(4-dimethylamino-4-phenyl-cyclohexyl)- N′-[2-(4-methoxy-phenoxy)-ethyl]- succinamide
298
Figure US08088763-20120103-C00301
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-[2-(ethyl-m-tolyl-amino)- ethyl]-succinamide
299
Figure US08088763-20120103-C00302
 		Glutaric acid-(4-benzyloxy-phenyl)-amide (4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-amide
300
Figure US08088763-20120103-C00303
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide[2-(4-fluoro- phenyl)-ethyl]-amide
301
Figure US08088763-20120103-C00304
 		Glutaric acid-[2-(4-bromo-phenyl)-ethyl]- amide (4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-amide
302
Figure US08088763-20120103-C00305
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-(4-phenoxy-phenyl)- succinamide
303
Figure US08088763-20120103-C00306
 		N-(4-dimethylamino-4-phenyl-cyclohexyl)- N′-[2-(3-trifluoromethyl-phenyl)-ethyl]- succinamide
304
Figure US08088763-20120103-C00307
 		Glutaric acid-[2-(4-chloro-phenyl)-propyl]- amide (4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-amide
305
Figure US08088763-20120103-C00308
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-[2-(1H-indol-3-yl)-ethyl]-N′- methyl-succinamide
306
Figure US08088763-20120103-C00309
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-[2-(4-methoxy-phenoxy)- ethyl]-succinamide
307
Figure US08088763-20120103-C00310
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (3-phenoxy-phenyl)- amide
308
Figure US08088763-20120103-C00311
 		N-(4-dimethylamino-4-phenyl-cyclohexyl)- N′-[2-(ethyl-m-tolyl-amino)-ethyl]- succinamide
309
Figure US08088763-20120103-C00312
 		Glutaric acid-[2-(5-bromo-2-methoxy- phenyl)-ethyl]-amide (4-dimethylamino-4- thiophen-2-yl-cyclohexyl)-amide
310
Figure US08088763-20120103-C00313
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-[2-(3-trifluoromethyl- phenyl)-ethyl]-succinamide
311
Figure US08088763-20120103-C00314
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (1-methyl-3-phenyl- propyl)-amide
312
Figure US08088763-20120103-C00315
 		N-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]- N′-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-succinamide
313
Figure US08088763-20120103-C00316
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (2,2-diphenyl- propyl)-amide
314
Figure US08088763-20120103-C00317
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-[3-(methyl-phenyl-amino)- propyl]-succinamide
315
Figure US08088763-20120103-C00318
 		N-(1-biphenyl-4-ylmethyl-pyrrolidin-3-yl)- N′-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N-methyl-succinamide
316
Figure US08088763-20120103-C00319
 		Glutaric acid-[4-(cyano-phenyl-methyl)- phenyl]-amide (4-dimethylamino-4- thiophen-2-ylcyclohexyl)-amide
317
Figure US08088763-20120103-C00320
 		Glutaric acid-(4-tert-butyl-cyclohexyl)- amide (4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-amide
318
Figure US08088763-20120103-C00321
 		Glutaric acid-(4-sec-butyl-phenyl)-amide (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
319
Figure US08088763-20120103-C00322
 		Glutaric acid-(4-butyl-phenyl)-amide (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
320
Figure US08088763-20120103-C00323
 		N-(2-benzylsulphanyl-ethyl)-N′-(4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- succinamide
321
Figure US08088763-20120103-C00324
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-(2-phenoxy-ethyl)- succinamide
322
Figure US08088763-20120103-C00325
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (naphthalen-1- ylmethyl)-amide
323
Figure US08088763-20120103-C00326
 		Glutaric acid-3-bromo-benzylamide (4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- amide
324
Figure US08088763-20120103-C00327
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-(3-phenyl-propyl)- succinamide
325
Figure US08088763-20120103-C00328
 		N-[2-(3-chloro-phenyl)-ethyl]-N′-(4- dimethylamino-4-phenyl-cyclohexyl)- succinamide
326
Figure US08088763-20120103-C00329
 		2-[3-(4-dimethylamino-4-thiophen-2-yl- cyclohexylcarbamoyl)-propionylamino]- propanoic acid benzylester
327
Figure US08088763-20120103-C00330
 		N-[2-(2-chloro-phenyl)-ethyl]-N′-(4- dimethylamino-4-phenyl-cyclohexyl)- succinamide
328
Figure US08088763-20120103-C00331
 		N-(4-dimethylamino-4-phenyl-cyclohexyl)- N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide
329
Figure US08088763-20120103-C00332
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (2-thiophen-2-yl- ethyl)-amide
330
Figure US08088763-20120103-C00333
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide[2-(4-phenoxy- phenyl)-ethyl]-amide
331
Figure US08088763-20120103-C00334
 		N-[2-(4-chloro-phenyl)-ethyl]-N′-(4- dimethylamino-4-phenyl-cyclohexyl)- succinamide
332
Figure US08088763-20120103-C00335
 		N-[2-(3-chloro-phenyl)-ethyl]-N′-(4- dimethylamino-4-thiophen-2-yl-cyclohexyl)- succinamide
333
Figure US08088763-20120103-C00336
 		N-benzyl-N′-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-N-ethyl-succinamide
334
Figure US08088763-20120103-C00337
 		Glutaric acid-[1-(2,6-dichloro-benzyl)- pyrrolidin-3-yl]-amide (4-dimethylamino-4- thiophen-2-yl-cyclohexyl)-amide
335
Figure US08088763-20120103-C00338
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (3-phenyl-propyl)- amide
336
Figure US08088763-20120103-C00339
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide[2-(1H-indol-3-yl)- ethyl]-amide
337
Figure US08088763-20120103-C00340
 		5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxo- valeric acid (4-dimethylamino-4-thiophen-2- yl-cyclohexyl)-amide
338
Figure US08088763-20120103-C00341
 		{[4-(4-dimethylamino-4-thiophen-2-yl- cyclohexylcarbamoyl)-butyryl]-methyl- amino}-acetic acid benzylester
339
Figure US08088763-20120103-C00342
 		N-(4-dimethylamino-4-thiophen-2-yl- cyclohexyl)-N′-[2-(4-phenoxy-phenyl)- ethyl]-succinamide
340
Figure US08088763-20120103-C00343
 		Glutaric acid-(4-dimethylamino-4-thiophen- 2-yl-cyclohexyl)-amide (2-phenyl- cyclopropyl)-amide
Selected examples have also been synthesised on a larger scale.
Example 341 N-[-(4-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-yl-methylsuccinic acid amide hydrochloride, non-polar diastereoisomer
A solution of 5.0 ml C-furan-2-yl-methylamine and 6.7 ml dilsopropylethylamine in 25 ml THF p.a. was added dropwise to 3.92 g succinic acid anhydride in 40 ml THF p.a. and the solution stirred over night. After addition of 25 ml two-molar hydrochloric acid, extraction was carried out three times with 40 ml dichloromethane in each case, the extracts dried over magnesium sulphate, filtered and evaporated. 7.0 g N-furan-2-yl-methylsuccinic acid were obtained.
1.0 g 1-(3-chlorobenzyl)-N,N-dimethylcyclohexane-1,4-diamine, obtained as a cis/trans-mixture from 4-(3-chlorobenzyl)-4-dimethylaminocyclohexanone by reaction with hydroxylamine and reduction of the oxime obtained with lithium aluminium hydride (WO 02090317), dissolved in 5 ml DMF, was added to 0.74 g N-furan-2-yl-methylsuccinic acid at 0° C. and 0.59 ml N,N-diisopropylcarbodiimide followed by 0.5 g 1-hydroxybenzotriazole (HOBt) were added while stirring. After 3 hours in an ice bath, the mixture was stirred overnight at room temperature. For working up, one-molar sodium carbonate solution was added (pH>10) and the crude product (1.75 g) was isolated by extraction with ethyl acetate/THF (V:V=1:1), with subsequent drying over sodium sulphate and evaporation. The main fraction, obtained after column chromatography on silica gel (3.0×20 cm) with 250 ml diethyl ether, diethyl ether/methanol (V:V=4:1) and diethyl ether/methanol (V:V=1:1), of 718 mg was dissolved in 50 ml 2-butanone, 50 ml ethyl acetate and 2 ml methanol and, by adding 29 μl water and 200 μl chlorotrimethylsilane, converted into the corresponding hydrochloride of the N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-yl-methylsuccinic acid amide (648 mg of white solid, mp. 233-234.5° C.).
Example 342 N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-yl-methylsuccinic acid amide hydrochloride, polar diastereoisomer
As described for Example 341, 357 mg of the polar diastereoisomer of N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-yl-methylsuccinic acid amide were also obtained, which, dissolved in 25 ml 2-butanone, were converted into the corresponding hydrochloride by adding 14.4 μl water and 100 μl chlorotrimethylsilane (230 mg of white solid, mp. 186-188° C.).
Example 343 Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(2-fluorophenyl)ethyl]amide hydrochloride, non-polar diastereoisomer
As described for Example 341, 0.95 mg 4-[2-(2-fluorophenyl)ethylcarbamoyl]butyric acid and 0.87 1-benzyl-N,N-dimethylcyclohexane-1,4-diamine were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.50 g 1-hydroxybenzotriazole and the crude product (1.65 g yellow solid) similarly isolated. 720 mg of the non-polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide was obtained by column chromatography on silica gel (3.0×20 cm) with 450 ml diethyl ether, followed by 450 ml diethyl ether/methanol (V:V=4:1) and 450 ml diethyl ether/methanol (V:V=1:1), was dissolved in 25 ml 2-butanone, 25 ml ethyl acetate and converted into the corresponding hydrochloride by adding 28 μl water and 198 μl chlorotrimethylsilane (657 mg of vitreous solid).
Example 344 Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(2-fluorophenyl)ethyl]amide hydrochloride, polar diastereoisomer
As described for Example 343, 260 mg of the polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide were also obtained, which were dissolved in 5 ml 2-butanone and 45 ml ethyl acetate and converted into the corresponding hydrochloride by adding 10 μl water and 71 μl chlorotrimethylsilane (110 mg of vitreous solid).
Example 345 N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]succinic acid amide hydrochloride, non-polar diastereoisomer
As described for Example 341, 0.96 mg N-[2-(4-chlorophenyl)ethyl]succinic acid and 1.0 g 4-(3-chlorobenzyl)-4-dimethylaminocyclohexanone were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.5 g 1-hydroxybenzotriazole and the crude product (2.23 g yellow solid) similarly isolated. 947 mg of the non-polar diastereoisomer of N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]succinic acid amide were obtained by column chromatography on silica gel (3.0×20 cm) with 200 ml diethyl ether, followed by 200 ml diethyl ether/methanol (V:V=5:1). 300 mg of this were dissolved in 5 ml 2-butanone, 10 ml ethyl acetate and 1 ml methanol and 10.7 μl water and 76 μl chlorotrimethylsilane were added, the batch evaporated to dryness, the residue stirred over 3 days at room temperature with 10 ml butanone and 10 diisopropylether and the precipitated hydrochloride isolated by filtration and dried (200 mg white solid).
Example 346 N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]succinic acid amide hydrochloride, polar diastereoisomer
As described for Example 345, 360 mg of the polar diastereoisomer of N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]succinic acid amide were also obtained, which were dissolved in 25 ml 2-butanone and 10 ml ethyl acetate and converted into the corresponding hydrochloride by adding 12.5 μl water, 88 μl chlorotrimethylsilane and 10 ml diisopropylether (236 mg of white solid, mp 186-187.5° C.).
Example 347 Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-4(-chlorophenyl)ethyl]amide hydrochloride, non-polar diastereoisomer
As described for Example 341, 0.87 mg 4-[2-(4-chlorophenyl)ethyl-carbamoyl]butyric acid and 1.0 g 4-benzyl-4-dimethylaminocyclohexanone were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.5 g 1-hydroxybenzotriazole and the crude product (1.80 g) similarly isolated. 900 mg of the non-polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-4(-chlorophenyl)ethyl] amide were obtained by chromatography on silica gel (3.0×20 cm) with 200 ml diethyl ether, followed by 200 ml diethyl ether/methanol (V:V=5:1), was dissolved in 20 ml 2-butanone and 20 ml ethyl acetate and converted into the corresponding hydrochloride by adding 33.5 μl water and 236 μl chlorotrimethylsilane and then evaporating to dryness (980 mg of vitreous solid).
Example 348 Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(4-chlorophenyl)ethyl]amide hydrochloride, polar diastereoisomer
As described for Example 347, 335 mg of the polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(4-chlorophenyl)ethyl]amide were obtained, which, dissolved in 30 ml 2-butanone, 30 ml ethyl acetate and 2 ml methanol, were converted into the corresponding hydrochloride by adding 12.5 μl water, 88 μl chlorotrimethylsilane and 10 ml diisopropylether (255 mg of white solid).
Tests on the Efficacy of the Compounds According to the Invention:
Measurement of ORL1 Binding
The cyclohexane derivatives of general formula I were examined in a receptor binding assay with 3H-nociceptin/orphanin FQ with membranes of recombinant CHO-ORL1 cells. This test system was carried out according to the methods presented by Ardati et al (Mol. Pharmacol., 51, 1997, pp. 816-824). The concentration of 3H-nociceptin/orphanin FQ was 0.5 nM in these tests. The binding assays were carried out with 20 μg membrane protein per 200 μl batch in 50 mM Hepes, pH 7.4, 10 mM MgCl2 and 1 mM EDTA. The binding with the ORL1 receptor was determined by using 1 mg WGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubation of the batch for one hour at RT and subsequent measurement in the Trilux scintillation counter (Wallac, Finland). The affinity is shown in Table 1 as a nanomolar Ki value in or % inhibition at c=1 μM.
Measurement of μ-Binding
The receptor affinity for human p-opiate receptor was determined in a homogenous batch in microtitre plates. For this purpose, dilution series of the respective substituted cyclohexyl-1,4-diamine derivative to be tested were incubated with a receptor membrane preparation (15-40 μg protein per 250 μl incubation batch) of CHO-K1 cells, which express the human μ-opiate receptor (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [3H]-naloxone (NET719, NEN, Zaventem, Belgium) and 1 mg WGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 μl for 90 minutes at room temperature. 50 mmol/l tris-HCI were added as an incubation buffer with 0.05% by weight sodium azide and 0.06% by weight bovine serum albumin. 25 μmol/l naloxone were also added to determine the non-specific binding. At the end of the 90-minute incubation period, the microtitre plates were centrifuged off for 20 minutes at 1000 g and the radioactivity measured in a β-counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of the radioactive ligand from its binding with the human p-opiate receptor at a concentration of the test substances of 1 μmol/l was determined and given as a percentage inhibition (% inhibition) of the specific binding. IC50 inhibition concentrations, which bring about a 50% displacement of the radioactive ligand, were partially calculated by taking as a basis the percentage displacement by various concentrations of the compounds of general formula I to be tested. Ki values for the test substances were obtained as a result of conversion by means of the Cheng-Prusoff equation.
Measurement of Serotonin Re-Uptake
In order to carry out these in vitro studies, synaptosomes were freshly isolated from areas of rats' brains. In each case, what is known as a “P2” fraction, which was prepared in accordance with Gray and Whittaker's directions (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88), was used. For the 5HT-uptake, these vesicular particles were isolated from the medulla+pons region of male rats' brains.
A detailed description of the method can be found in the literature (M. Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).
Measurement of Noradrenalin Re-Uptake
In order to carry out these in vitro studies, synaptosomes were freshly isolated from rat brain areas. In each case, what is known as a “P2” fraction, which was prepared in accordance with Gray and Whittaker's directions (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88), was used. For the NA-uptake, these vesicular particles were isolated from the hypothalamus of male rats' brains.
A detailed description of the method can be found in the literature (M. Ch. Frink, H. H. Hennies, W. Englberger, M. Haurand and B. Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).
The following binding data was determined, by way of example:
ORL1-binding, [1 μM],
Example % inhibition
249 49
250 76
251 96
252 88
253 92
254 88
255 69
256 95
257 94
258 68
259 73
260 80
261 90
262 57
263 79
264 99
265 77
266 96
267 95
268 98
269 86
270 92
271 78
272 39
273 96
274 64
275 85
276 98
277 86
278 96
279 82
280 96
281 77
282 82
283 76
284 84
285 99
286 72
287 79
288 75
289 86
290 95
291 78
292 93
293 81
294 100
295 98
296 97
297 74
298 73
299 90
300 95
301 99
302 72
303 99
304 98
305 99
306 72
307 98
308 71
309 100
310 98
311 90
312 100
313 71
314 88
315 60
316 77
317 91
318 94
319 97
320 98
321 90
322 98
323 97
324 96
325 98
326 91
327 93
328 94
329 97
330 99
331 92
332 98
333 92
334 95
335 94
336 99
337 96
338 98
339 98
340 84
μ-binding, [1 μM],
Example % inhibition
15 59
31 53
40 57
42 64
55 50
59 55
63 65
64 67
66 57
69 58
74 56
76 54
77 62
78 54
80 51
82 60
90 89
95 56
97 59
110 55
115 59
116 50
117 68
118 59
119 70
120 58
121 50
124 80
125 87
127 64
128 64
129 56
130 60
131 66
132 70
136 62
141 58
142 70
143 57
144 67
145 66
146 58
147 66
148 64
149 54
150 67
151 90
152 68
153 67
154 57
155 66
156 69
157 54
159 80
160 62
161 52
162 50
163 51
164 58
167 59
169 60
170 68
171 67
172 58
173 90
174 72
175 84
176 56
177 56
178 60
179 56
180 59
181 50
182 53
183 61
184 51
185 57
186 55
187 53
188 50
189 61
190 54
191 59
192 54
193 51
194 68
195 51
196 50
197 74
198 62
199 50
200 55
201 69
202 67
203 56
204 52
205 51
206 56
207 57
208 50
209 67
210 57
211 56
212 77
213 73
214 58
215 54
216 65
217 54
218 62
219 60
5HT-uptake [10 μM],
Example % inhibition
1 93
2 95
3 94
4 92
5 93
6 96
7 93
8 92
9 93
10 92
11 92
12 92
13 92
14 95
15 92
16 97
17 93
18 94
19 93
20 92
21 95
22 95
23 92
24 92
25 97
26 93
27 95
28 92
29 94
30 93
31 97
32 99
33 95
34 97
35 94
36 96
37 95
38 95
39 94
40 94
41 92
42 97
43 98
44 94
45 92
46 92
47 93
48 94
49 92
50 92
51 92
52 96
53 93
54 95
56 95
57 93
58 93
60 93
61 92
62 100
63 94
64 96
65 92
66 94
67 98
68 98
70 93
71 92
72 95
73 93
74 96
75 97
76 96
79 96
81 92
82 92
83 93
84 95
85 94
86 92
87 96
88 97
89 94
90 96
91 92
92 92
93 92
94 92
95 93
96 94
98 92
99 94
100 92
101 94
102 94
103 94
104 93
105 92
106 93
107 95
108 94
110 100
111 96
112 96
113 97
114 99
122 93
123 92
126 93
133 93
134 92
135 92
137 94
138 92
139 93
140 93
141 94
165 92
168 92
NA-uptake [10 μM],
Example % inhibition
1 71
2 87
3 89
4 89
5 80
6 91
7 91
8 85
9 91
10 78
11 77
12 95
13 72
14 78
15 85
16 86
17 82
18 84
19 74
20 90
21 83
22 93
23 92
24 91
25 95
26 79
27 92
28 81
29 91
30 96
31 102
32 97
33 99
34 87
35 95
36 93
37 100
38 79
39 90
40 96
41 90
42 97
43 96
44 84
45 77
46 89
47 73
48 97
49 98
50 89
51 77
52 88
53 94
54 90
56 96
57 100
58 79
60 71
61 93
62 86
63 94
64 102
65 84
66 92
67 96
68 85
70 96
71 94
72 70
73 87
74 98
75 99
76 101
79 95
81 91
82 94
83 105
84 96
85 100
86 76
87 94
88 102
89 98
90 109
91 101
92 89
93 75
94 86
95 99
96 87
98 74
99 99
100 77
101 77
102 105
103 108
104 84
105 90
106 98
107 106
108 100
110 95
111 97
112 101
113 94
114 106
122 102
123 99
126 84
133 97
134 101
135 96
137 83
138 84
139 95
140 77
141 99
165 94
168 96
Parenteral Solution of a Substituted cyclohexyl-1,4-diamine Derivative According to the Invention
38 g of one of the substituted cyclohexyl-1,4-diamine derivatives according to the invention, here Example 1, were dissolved at room temperature in 1 l water for injection purposes and then adjusted to isotonic conditions for injection purposes by adding anhydrous glucose.
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

Claims (28)

1. A cyclohexyl-1,4-diamine compound corresponding to formula I,
Figure US08088763-20120103-C00344
wherein
n represents 1, 2, 3, 4 or 5
R1 and R2 independently of one another represent H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
or R1 and R2 together form a ring and represent CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6,
wherein R10 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl singly or multiply substituted or unsubstituted C3-8 cycloalkyl; singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl; substituted or unsubstituted C(O)phenyl, C(O)heteroaryl, C(O)C1-5 alkyl;
R3 represents saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; unsubstituted or singly or multiply substituted aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkyl group;
R4 represents —(CR6R7)pR8,
wherein p represents 0, 1, 2, 3 or 4;
R6 represents H or saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl;
R7 represents H, saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl or COOR9;
or R6 and R7 together form a ring and represent (CH2)kCHR8(CH2)m, where k =1, 2, or 3 and m =1 or 2;
R8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl; unsubstituted or singly or multiply substituted C3-8 cycloalkyl, aryl or heteroaryl;
R9 represents H or C1-5 alkyl;
R5 represents H or —(CH2)1R8,
wherein l represents 1, 2 or 3 or R5 and R4 together form a ring and represent CH2CHR14OCHR14CH2, CH2CH2SCH2CH2
CH2CH2NR11CH2CH2, (CR12R13)3-6 or
Figure US08088763-20120103-C00345
wherein R11 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
R12 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; OH; unsubstituted or singly or multiply substituted C(O)phenyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
and R13 represents H or OH or together with R12 via the same C atom or an adjacent C atom forms a five-membered or six-membered ring which may contain heteroatoms, be saturated or unsaturated, substituted or unsubstituted or be part of a polycyclic system;
R14 represents respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-3 alkyl;
or an acid, base or a physiologically acceptable salt thereof.
2. The compound of claim 1, wherein said compound is present in the form of a pure enantiomer or pure diastereoisomer.
3. The compound of claim 1, wherein said compound is present in the form of a mixture of stereoisomers.
4. The compound of claim 1, wherein said compound is present in the form of a racemic mixture.
5. A cyclohexyl-1,4-diamine compound according to claim 1, wherein
R1 and R2 independently of one another represent H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl;
or R1 and R2 together form a ring and represent CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6,
wherein R10 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl.
6. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R1 and R2 independently of one another represent CH3 or H, wherein R1 and R2 do not simultaneously represent H, or R1 and R2 together form a ring and represent CH2CH2OCH2CH2 or (CH2)6.
7. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R3 represents unsubstituted or singly or multiply substituted cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl; respectively unsubstituted or singly or multiply substituted C5-6 cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bound by a saturated, unbranched C1-2 alkyl.
8. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R3 represents unsubstituted or singly or multiply substituted phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyridyl, pyrimidyl, pyrazinyl or benzothiophenyl; unsubstituted or singly or multiply substituted phenyl, furyl or thiophenyl bound by a saturated, unbranched C1-2 alkyl group.
9. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R3 represents substituted or unsubstituted phenyl, thiophenyl, pyridyl or benzyl, more preferably 4-methylbenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-methylbenzyl, benzyl, phenyl, thiophenyl or 3-fluorophenyl.
10. A cyclohexyl-1,4-diamine compound according to claim 1, wherein n represents 2 or 3.
11. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R 4 represents —(CR6R7)pR8 and R5 represents H.
12. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R4 represents (CH2)pR8 and R5 represents —(CH2)lR8.
13. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R4 and R5 together represent CH2CHR14OCHR14CH2, CH2CH2SCH2CH2,
CH2CH2NR11CH2CH2 (CR12R13)3-6 or
Figure US08088763-20120103-C00346
14. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R6 represents H and R7 represents H, CH3, unsubstituted or singly or multiply substituted benzyl, or COOR9 or R6 and R7 together form a ring and represent (CH2)kCHR8(CH2)m.
15. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R8 represents saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl; unsubstituted or singly or multiply substituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyrrolidinyl, tetrahydrofuryl, piperazinyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl.
16. A cyclohexyl-1,4-diamine compound according to claim 1, wherein R8 represents saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl; unsubstituted or singly or multiply substituted pyrrolidinyl, morpholinyl, tetrahydrofuryl, tetrahydronaphthyl, dihydroindolyl, pyridyl, thienyl, piperazinyl, naphthyl, indanyl, quinolinyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, furyl, benzofuryl, phenyl or indolyl.
17. A cyclohexyl-1,4-diamine compound according to claim 1, wherein said compound is selected from the group consisting of:
N-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-oxo-tetrahydro-furan-3-yl)-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,3-diphenyl-propyl)-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(7-methoxy-benzo[1,3]dioxol-5-yl-methyl)-piperazin-1-yl]-4-oxo-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(3,6-dihydro-2H-pyridin-1-y1)-4-oxo-butyramide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-m-tolyl-piperazin-1-yl)-butyramide;
2-{3-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-propanoic acid ethylester;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-4-oxo-butyramide;
3-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-propanoic acid ethylester;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin -1-yl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-methyl-N′-[2-(2,2,2-trifluoro-acetylamino)-ethyl ]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-pyridin-2-yl-ethyl)-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-thiomorpholin-4-yl-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin -1-yl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-thiophen-2-yl-ethyl)-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(4-ethoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide;
N-allyl-N′-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-methyl-succinamide;
5-[4-(2,5-dimethoxy-benzyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
4-(3,6-dihydro-2H-pyridin-1-yl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4-oxo-butyramide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-pyridin-2-yl-piperazin-1-yl)-butyramide;
({3-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-propionyl}-methyl-amino)-acetic acid benzyl ester;
4-[4-(2,6-dichloro-benzyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
{[4-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-butyryl]-methyl-amino}-acetic acid tert butyl ester;
5-[4-(2-fluoro-5-methoxy-benzyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-methoxy-propyl)-succinamide;
4-[4-(4-acetyl-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
4-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionyl}-piperazin-1-carboxylic acid-tert-butylester;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(tetrahydro-furan-2-ylmethyl)-succinamide;
2-{3-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-propanoic acid ethylester;
N-(3-bromo-benzyl)-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
3-(4-chloro-phenyl)-2-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-prop anoic acid methylester;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin-1-yl]-4-oxo-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-naphthalen-1-ylmethyl-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-[4-(3-fluoro-4-methoxy-benzyl)-piperazin-1-yl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexy]N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide;
(4-{3-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-benzyl)-phosphonic acid diethylester;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-methyl-N′-(2-pyridin-2-yl-ethyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(3,6-dihydro-2H-pyridin-1-yl)-4-oxo-butyramide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)-succinamide;
5-[4-(5-methyl-pyrazin-2-carbonyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-chloro-6-methyl-benzyl)-succinamide;
N-allyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-methyl-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-cyclopentyl-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(tetrahydro-furan-2-ylmethyl)-succinamide;
(4-{3-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-benzyl)-phosphonic acid diethylester;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-[4-(3-methoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,5-difluoro-benzyl)-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-methyl-benzyl)-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-{4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidin-1-yl}-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide;
5-[4-(7-methoxy-benzo[1,3]dioxo1-5-ylmethyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohex)/1)-amide;
N-benzyl-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-(2-hydroxy-ethyl)-succinamide;
5-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-4-oxo-butyramide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-methyl-piperidin-1-yl)-4-oxobutyramide;
2-{3-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-propanoic acid-tert-butylester;
5-(4-cycloheptyl-piperazin-1-yl)-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(4-fluoro-phenyl)-ethyl]-amide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-amide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-oxo-butyramide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-thiomorpholin-4-yl-butyramide;
4-(4-benzoyl-piperidin-1-yl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,4-dimethoxy-benzyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-ethyl-N′-pyridin-4-ylmethyl-succinamide;
N-[2-(3,4-dimethoxy-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-methyl-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-methyl-N′-pyridin-3-ylmethyl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-pyridin-2-ylmethyl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-methyl-benzyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(4-methoxy-phenyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-indan-2-yl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)-succinamide;
N-(2-chloro-6-methyl-benzyl)-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-[2-(4-fluoro-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide 4-dimethylamino-benzylamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,5-dichloro-benzyl)-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-methyl-3-phenyl-propyl)-succinamide;
4-{3-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionyl}-piperazin-1-carboxylic acid ethylester;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(4-methoxy-benzyl)-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(2,6-dimethyl-morpholin-4-y1)-4-oxo-butyramide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide;
4-[4-(4-allyloxy-benzyp-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(5-bromo-2-methoxy-phenyl)-ethyl]-amide;
5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-(3-chloro-benzyl)- 4- dimethylamino-cyclohexyl]- 4-(4-methyl-piperidin-1-yl)-4-oxo-butyramide;
(4-{3-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-propionylamino}-benzyl)-phosphonic acid diethylester;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-o-tolyl-piperazin-1-y1)-butyramide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide;
4-[4-(4-chloro-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[1-(4-fluoro-phenyl)-ethyl]-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[1-(4-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-5-yl-succinamide;
N-(4-benzyloxy-phenyl)-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide;
2-{3-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-propionylamino}-3-methyl-valeric acid tert-butyl ester;
4-(4-benzyl-piperidin-1-yl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(1,2-dimethyl-propyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indo1-2-yl)-4-oxo-butyramide, 4-[4-(3-chloro-benzoyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(4-methoxy-phenyl)-succinamide;
5-[4-(2,6-dichloro-benzyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[1-(4-fluoro-phenyl)-ethyl]-succinamide;
4-[4-(4-chloro-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl)-butyramide;
N-benzyl-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-methyl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,5-difluoro-benzyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(4-fluoro-phenyl)-ethyl]-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(1H-indo1-3-yl)-ethyl]-succinamide;
N-(2-benzylsulphanyl-ethyl)-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,4-difluoro-benzyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-phenethyl-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1-naphthalen-2-yl-ethyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-methoxymethyl-2-phenyl-ethyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,4-dichloro-benzyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-furan-2-ylmethyl-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(1,2,3,4-tetrahydro-naphthalen-1 -yl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(4-fluoro-benzyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-be nzyl)-cyclohexyl]-N′-indan-1-yl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(3,5-dimethyl-piperidin-1-yl )-4-oxo-butyramide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-phenethyl-succinamide; N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-phenethyl-succinamide;
N-(2-benzylsulphanyl-ethyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,5-dichloro-benzyl)-succinamide;
4-[4-(3-chloro-benzoyl)-piperazin-1-yl]-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-phenyl-propyl)-succinamide;
N-(4-bromo-2-fluoro-benzyl)-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-methyl-N′-pyridin-3-ylmethyl-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(2-ethoxy-benzyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohhexyl]-N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-succinamide;
N-(4-sec-butyl-phenyl)-N′-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
5-oxo-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
5-oxo-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide;
N-(3-bromo-benzyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
N-(4-bromo-2-fluoro-benzyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-phenyl-propyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(4-fluoro-2-trifluoromethyl-benzyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-2-yl-succinhmide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-butyramide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(2-fluoro-phenyl)-ethyl]-amide;
N-[2-(2-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cycloheXyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3,4-difluoro-benzyl)-succinamide;
N-benzyl-N-(2-cyano-ethyl)-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-methyl-benzyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(4-fluoro-3-trifluoromethyl-benzyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-chloro-phenyl)-ethyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(4-chloro-phenyl)-ethyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2,4-dichloro-phenyl)-ethyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-1-yl-succinamide;
N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-indan-1-yl-succinamide;
N-[2-(4-chloro-phenyl)-propyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-(3-bromo-benzyl)-N′-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-phenyl-propyl)-succinamide;
N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-N′-(2-p-tolyl-ethyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-thiophen-2-yl-ethyl)-succinamide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(4-chloro-phenyl)-propyl]-amide;
N-benzyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-methyl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-chloro-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(2-ethoxy-phenyl)-ethyl]-amide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide phenethyl-amide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide [2-(3-chloro-phenyl)-ethyl]amide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[1-(3-methoxy-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-benzyl-4-dimethylamino-cyclohexyl)-amide (1,3-dimethyl-butyl)-amide;
N-benzyl-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N-ethyl-succinamide;
N-(4-chloro-benzyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-fluoro-phenyl)-ethyl]-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-fluoro-benzyl)-succinamide;
N-[2-(4-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-[2-(2-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-[2-(3-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-benzyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-(2-cyano-ethyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-chloro-4-fluoro-benzyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-trifluoromethyl-benzyl)-succinamide;
N-[2-(2,4-dichloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-benzyl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N-ethyl-succinamide;
N-[2-(4-chloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide;
5-oxo-5-(4-o-tolyl-piperazin-1-yl)-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[3-(methyl-phenyl-amino)-propyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-4-oxo-butyramide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-[2-(2-ethoxy-phenyl)-ethyl]-succinamide;
4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-butyramide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2-ethoxy-phenyl)-ethyl]-succinamide;
N-[2-(2,6-dichloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-benzhydryl-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-cyclooctyl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(4-phenoxy-phenyl)-ethyl]-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2,3-dimethyl-benzyl)-succinamide;
4-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-succinamide;
N-(2-chloro-benzyl)-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-(2-chloro-benzyl)-N′-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(3-fluoro-5-trifluoromethyl-benzyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-p-tolyl-ethyl)-succinamide;
N-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]-N′-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-[2-(3-trifluoromethyl-phenyl)-ethyl]-succinamide;
N-[2-(3,4-dichloro-phenyl)-ethyl]-N′-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-[4-(2-fluoro-phenyl)-piperazin-1-yl]-4-oxo-butyramide;
5-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-5-oxo-valeric acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(1-naphthalen-1-yl-ethyl)-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(1-naphthalen-1-yl-ethyl)-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2-fluoro-benzyl)-N′-furan-2-ylmethyl-succinamide;
N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-N′-(2-fluoro-benzyl)-N′-furan-2-ylmethyl-succinamide;
N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-N′-(2,5-dimethoxy-benzyl)-N′-furan-2-ylmethyl-succinamide;
N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-4-(2,3-dihydro-indo1-1-yl)-4-oxo-butyramide;
4-(2,3-dihydro-indol-1-yl)-N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-4-oxo-butyramide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2-chloro-6-methyl-benzyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(3-methoxy-phenyl)-ethyl]-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3-methyl-benzyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(4-bromo-2-fluoro-benzyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-pyridin-4-ylmethyl-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-indan-1-yl-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2,4-dimethoxy-benzyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-thiophen-2-ylmethyl-succinamide;
N-adamantan-1-ylmethyl-N′-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2,5-difluoro-benzyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(4-tert-butyl-phenyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3,5-bis-trifluoromethyl-benzyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(2-ethoxy-phenyl)-ethyl]-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3-methoxy-propyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2-morpholin-4-yl-ethyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2,5-dichloro-benzyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[1-(2-benzyloxy-benzyl)-pyrrolidin-3-yl]-N′-methyl-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-oxo-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-butyramide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-morpholin-4-yl-4-oxo-butyramide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(3-dimethylamino-propyl)-N′-methyl-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-(2-phenyl-cyclopropyl)-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-naphthalen-1-ylmethyl-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-butyramide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-(4-hydroxy-piperidin-1-yl)-4-oxo-butyramide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(7-methyl-1H-indol-3-yl)-ethyl]-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-N′-[2-(5-methoxy-1H-indo1-3-yl)-ethyl]-succinamide;
N-(4-benzyl-4-morpholin-4-yl-cyclohexyl)-4-oxo-4-(4-quinolin-2-ylmethyl-piperazin-1-yl)-butyramide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-oxo-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-butyramide;
Glutaric acid-(1-adamantan-1-yl-ethyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
N-[2-(2,6-dichloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(1-methyl-3-phenyl-propyl)-succinamide;
N-benzyl-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N-ethyl-succinamide;
N-[2-(4-bromo-phenyl)-ethyl]-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide;
4-[4-(4-chloro-benzoyl)-piperidin-1-yl]-N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-oxo-butyramide;
Glutaric acid-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3-phenyl-propyl)-amide;
N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-pentyl-succinamide;
3-(4-chloro-phenyl)-2-[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyrylamino]-propanoic acid ethylester;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide indan-1-ylamide;
N-adamantan-1-ylmethyl-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide;
5-(4-benzofuran-2-ylmethyl-piperazin-1-yl)-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
4-[4-(4-tert-butyl-benzyl)-piperazin-1-yl]-N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-oxo-butyramide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(1H-indo1-3-y1)-ethyl]-amide;
N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-4-oxo-butyramide;
5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
4-(4-benzyl-pip eridin-1-yl)-N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-oxo-butyramide;
{[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyryl]-methyl-amino}-acetic acid benzylester;
N-benzyl-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-N-phenethyl-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide 3-trifluoromethoxy-benzylamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide ethyl-(2-methyl-allyl)-amide;
N,N-bis-(2-cyano-ethyl)-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide;
Glutaric acid-benzyl-methyl-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(2-benzyloxy-cyclopentyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide 4-trifluoromethyl-benzylamide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(4-phenoxy-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3,3-diphenyl-propyl)-amide;
4-(4-benzyl-piperidin-1-yl)-N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-oxo-butyramide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-4-oxo-butyramide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide 4-fluoro-2-trifluoromethyl-benzylamide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-pentyl-succinamide;
5-[4-(2-methoxy-naphthalen-1-ylmethyl)-piperazin-1-yl]-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(2-ethoxy-benzyl)-N′-furan-2-ylmethyl-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2-phenyl-cyclopropyl)-amide;
N-[2-(3,4-dichloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide;
N-adamantan-1-ylmethyl-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide;
5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
2-[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyrylamino]-4-methyl-valeric acid benzyl ester;
{4-[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyrylamino]-phenyl}-carbamic acid-tert-butylester;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(3-methoxy-phenyl)-ethyl]-amide;
Glutaric acid-benzyl-ethyl-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-3-chloro-benzylamide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (4-methyl-cyclohexyl)-amide;
N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide;
Glutaric acid-2,5-dichloro-benzylamide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(3-fluoro-phenyl)-ethyl]-amide;
N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(4-methoxy-phenoxy)-ethyl]-succinamide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(ethyl-m-tolyl-amino)-ethyl]-succinamide;
Glutaric acid-(4-benzyloxy-phenyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(4-fluoro-phenyl)-ethyl]-amide;
Glutaric acid-[2-(4-bromo-phenyl)-ethyl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(4-phenoxy-phenyl)-succinamide;
N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(3-trifluoromethyl-phenyl)-ethyl]-succinamide;
Glutaric acid-[2-(4-chloro-phenyl)-propyl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(1H-indol-3-yl)-ethyl]-N′-methyl-succinamide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(4-methoxy-phenoxy)-ethyl]-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3-phenoxy-phenyl)-amide;
N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(ethyl-m-tolyl-amino)-ethyl]-succinamide;
Glutaric acid-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(3-trifluoromethyl-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (1-methyl-3-phenyl-propyl)-amide;
N-[2-(2,6-dichloro-benzylsulphanyl)-ethyl]-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2,2-diphenyl-propyl)-amide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[3-(methyl-phenyl-amino)-propyl]-succinamide;
N-(1-biphenyl-4-ylmethyl-pyrrolidin-3-yl)-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N-methyl-succinamide;
Glutaric acid-[4-(cyano-phenyl-methyl)-phenyl]-amide (4-dimethylamino-4-thiophen-2-ylcyclohexyl)-amide;
Glutaric acid-(4-tert-butyl-cyclohexyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-sec-butyl-phenyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-butyl-phenyl)-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
N-(2-benzylsulphanyl-ethyl)-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(2-phenoxy-ethyl)-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (naphthalen-1-ylmethyp-amide;
Glutaric acid-3-bromo-benzylamide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-(3-phenyl-propyl)-succinamide;
N-[2-(3-chloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide;
2-[3-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-propionylamino]-; propanoic acid benzylester;
N-[2-(2-chloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide;
N-(4-dimethylamino-4-phenyl-cyclohexyl)-N′-[2-(3-fluoro-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2-thiophen-2-yl-ethyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(4-phenoxy-phenyl)-ethyl]-amide;
N-[2-(4-chloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-phenyl-cyclohexyl)-succinamide;
N-[2-(3-chloro-phenyl)-ethyl]-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-succinamide;
N-benzyl-N′-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N-ethyl-succinamide;
Glutaric acid-[1-(2,6-dichloro-benzyl)-pyrrolidin-3-yl]-amide (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (3-phenyl-propyl)-amide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide [2-(1H-indo1-3-yl)-ethyl]-amide;
5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxo-valeric acid (4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide;
{[4-(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-butyryl]-methyl-amino}-acetic acid benzylester;
N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-N′-[2-(4-phenoxy-phenyl)-ethyl]-succinamide;
Glutaric acid-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-amide (2-phenyl-cyclopropyl)-amide;
N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-ylmethylsuccinic acid amide hydrochloride, non-polar diastereoisomer;
N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-ylmethylsuccinic acid amide hydrochloride, polar diastereoisomer;
Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(2-fluorophenyl)ethyl]amide hydrochloride, non-polar diastereoisomer;
Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(2-fluorophenyl)ethyl]amide hydrochloride, polar diastereoisomer;
N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]-succinic acid amide hydrochloride, non-polar diastereoisomer;
N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-[2-(4-chlorophenyl)ethyl]-succinic acid amide hydrochloride, polar diastereoisomer; and
Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide [2-(4-chlorophenyl)ethyl]amide hydrochloride, non-polar diastereoisomer.
18. A process for preparing a cyclohexyl-1,4-diamine compound according to claim 1, comprising the steps of:
linking a cyclohexane-1,4-diamine compound to a primary or secondary amine via an anhydride, open-chain dicarboxylic acid or an activated analog thereof.
19. The method of claim 18, wherein said activated analog is an acid halide.
20. A process for preparing a cyclohexyl-1,4-diamine compound according to claim 1, comprising the steps of:
reacting one or more coupling agents to link an anhydride, open-chain dicarboxylic acid or an activated analog thereof with a primary or secondary amine and
linking a substituted cyclohexane-1,4-diamine thereto.
21. The method of claim 20, wherein said activated analog is an acid halide.
22. A pharmaceutical formulation comprising at least one cyclohexyl-1,4-diamine compound according to claim 1 and one or more physiologically acceptable auxiliary substances.
23. A method of producing a pharmaceutical formulation comprising the steps of combining a pharmaceutically effective amount of a cyclohexyl-1,4-diamine compound according to claim 1 and one or more physiologically acceptable auxiliary substances.
24. A method of treating pain in a mammal, said method comprising administering to said mammal an effective amount of a compound according to claim 1.
25. The method of claim 24, wherein said pain is acute, neuropathic or chronic pain.
26. A method of treating a condition selected from the group consisting of anxiety, stress and stress-related syndromes, depression, epilepsy, withdrawal symptoms, alcohol abuse or dependency, drug abuse or dependency, medicine abuse or dependency, sexual dysfunction, hypotension, hypertension, tinnitus, pruritus, migraine, deficient intestinal motility, impaired nutrient absorption, anorexia, obesity, diarrhea, cachexia, urinary incontinence, or providing a muscle relaxant, nootropic, anti-convulsive or anaesthetic or for co-administration in treatment with an opioid analgesic or anaesthetic, for diuresis or anti-natriuresis, anxiolysis, for the treatment of withdrawal symptoms or for reducing opioid addiction potential, said method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound according to claim 1.
27. A cyclohexyl-1,4-diamine compound corresponding to formula I,
Figure US08088763-20120103-C00347
wherein
n represents 1, 2, 3, 4 or 5
R1 and R2 independently of one another represent H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
or R1and R2 together form a ring and represent CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6,
wherein R10 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl singly or multiply substituted or unsubstituted C3-8 cycloalkyl; singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl; substituted or unsubstituted C(O)phenyl, C(O)heteroaryl, C(O)C1-5 alkyl;
R3 represents saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; unsubstituted or singly or multiply substituted aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkyl group;
R4 represents —(CR6R7)pR8,
wherein p represents 0, 1, 2, 3 or 4;
R6 represents H or saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl;
R7 represents H, saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl or COORS9;
or R6 and R7 together form a ring and represent (CH2)kCHR8(CH2)m, where k =1, 2, or 3 and m =1 or 2;
R8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl; unsubstituted or singly or multiply substituted C3-8 cycloalkyl, aryl or heteroaryl;
R9 represents H or C1-5 alkyl;
R5 represents H or —(CH2)lR8,
wherein l represents 1, 2 or 3
or R5 and R4 together form a ring and represent CH2CHR14CHR14CH2, CH2CH2SCH2CH2
CH2CH2NR11CH2CH2, (CR12R13)3-6 or
Figure US08088763-20120103-C00348
wherein R11 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
R12 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; OH; unsubstituted or singly or multiply substituted C(O)phenyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
and R13 represents H or OH or together with R12 via the same C atom (spiro compound) or an adjacent C atom forms a five-membered or six-membered ring which may contain heteroatoms, be saturated or unsaturated, substituted or unsubstituted or be part of a polycyclic system;
R14 represents respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-3 alkyl;
or an acid, base, or a physiologically acceptable salt thereof.
28. A cyclohexyl-1,4-diamine compound corresponding to formula I,
Figure US08088763-20120103-C00349
wherein
n represents 1, 2, 3, 4 or 5
R1 and R2 independently of one another represent H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
or R1 and R2 together form a ring and represent CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6,
wherein R10 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl singly or multiply substituted or unsubstituted C3-8 cycloalkyl; singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl; substituted or unsubstituted C(O)phenyl, C(O)heteroaryl, C(O)C1-5 alkyl;
R3 represents saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; unsubstituted or singly or multiply substituted aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkyl group;
R4 represents —(CR6R7)pR8,
wherein p represents 0, 1, 2, 3 or 4;
R6 represents H or saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl;
R7 represents H, saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl or COOR9;
or R6 and R7 together form a ring and represent (CH2)kCHR8(CH2)m, where k=1, 2, or 3 and m=1 or 2;
R8 represents respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-6 alkyl; unsubstituted or singly or multiply substituted C3-8 cycloalkyl, aryl or heteroaryl;
R9 represents H or C1-5 alkyl;
R5 represents H or —(CH2)lR8,
wherein l represents 1, 2 or 3
or R5 and R4 together form a ring and represent CH2CHR14OCHR14CH2,
CH2CH2SCH2CH2, CH2CH2NR11CH2CH2, (CR,12R13)3-6 or
Figure US08088763-20120103-C00350
wherein R11 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
R12 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; OH; unsubstituted or singly or multiply substituted C(O)phenyl; singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;
R13 represents H or OH or together with R12 via the same C atom or an adjacent C atom forms a five-membered or six-membered ring which may contain heteroatoms, be saturated or unsaturated, substituted or unsubstituted or be part of a polycyclic system; and
R14 represents respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-3 alkyl;
or an acid, base, or a physiologically acceptable salt thereof.
US11/594,963 2004-05-10 2005-05-06 Cyclohexyl-1, 4-diamine compounds Expired - Fee Related US8088763B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102004023522 2004-05-10
DE102004023522A DE102004023522A1 (en) 2004-05-10 2004-05-10 Substituted cyclohexyl-1,4-diamine derivatives
DE102004023522.8 2004-05-10
PCT/EP2005/004913 WO2005110974A1 (en) 2004-05-10 2005-05-06 Substituted cyclohexyl-1,4-diamine derivatives

Publications (2)

Publication Number Publication Date
US20070112007A1 US20070112007A1 (en) 2007-05-17
US8088763B2 true US8088763B2 (en) 2012-01-03

Family

ID=34967002

Family Applications (1)

Application Number Title Priority Date Filing Date
US11/594,963 Expired - Fee Related US8088763B2 (en) 2004-05-10 2005-05-06 Cyclohexyl-1, 4-diamine compounds

Country Status (13)

Country Link
US (1) US8088763B2 (en)
EP (1) EP1745010B1 (en)
JP (1) JP5037337B2 (en)
AT (1) ATE438617T1 (en)
CA (1) CA2566297C (en)
CY (1) CY1109569T1 (en)
DE (2) DE102004023522A1 (en)
DK (1) DK1745010T3 (en)
ES (1) ES2333026T3 (en)
PL (1) PL1745010T3 (en)
PT (1) PT1745010E (en)
SI (1) SI1745010T1 (en)
WO (1) WO2005110974A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110059999A1 (en) * 2008-03-27 2011-03-10 Grünenthal GmbH Hydroxymethylcyclohexylamines

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004023501A1 (en) * 2004-05-10 2005-12-01 Grünenthal GmbH Oxo-substituted cyclohexyl-1,4-diamine derivatives
JP2010509392A (en) * 2006-11-13 2010-03-25 ファイザー・プロダクツ・インク Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof
PE20121313A1 (en) 2008-03-27 2012-10-07 Gruenenthal Chemie SUBSTITUTED 4-AMINOCICLOHEXANE DERIVATIVES
PE20091823A1 (en) 2008-03-27 2009-12-10 Gruenenthal Chemie SUBSTITUTE CYCLOHEXYL DIAMINES
US8293758B2 (en) 2008-03-27 2012-10-23 Grunenthal Gmbh Substituted spirocyclic cyclohexane derivatives
ES2544488T3 (en) 2008-03-27 2015-08-31 Grünenthal GmbH Derivatives of (hetero) aryl-cyclohexane
US8288430B2 (en) 2008-03-27 2012-10-16 Grunenthal Gmbh Spiro(5.5)undecane derivatives
CN116554127B (en) * 2022-01-28 2025-03-21 成都麻沸散医药科技有限公司 Piperazine substituted phenol derivatives and uses thereof
CN117430522A (en) * 2022-07-14 2024-01-23 浙江友宁生物医药科技有限公司 GPR139 receptor agonist and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002090317A1 (en) 2001-05-09 2002-11-14 Grünenthal GmbH Substituted cyclohexane-1,4-diamine derivatives
US20030229119A1 (en) 2002-02-22 2003-12-11 Kym Philip R. Antagonists of melanin concentrating hormone effects on the melanin concetrating hormone receptor

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4552200A (en) * 1999-05-12 2000-12-05 Solvay Pharmaceuticals B.V. Method of treating psychotic disorders
ES2188344B1 (en) * 2000-11-29 2004-09-16 Laboratorios Vita, S.A. COMPOUNDS DERIVED FROM BENZOTIOPHENE, ITS PROCEDURE FOR OBTAINING AND USING THEMSELVES.
NZ533217A (en) * 2001-12-21 2006-02-24 Lundbeck & Co As H Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors
DE10252666A1 (en) * 2002-11-11 2004-08-05 Grünenthal GmbH N-piperidyl-cyclohexane derivatives
DE10252650A1 (en) * 2002-11-11 2004-05-27 Grünenthal GmbH New 1,4-disubstituted cyclohexylamine derivatives, are opioid receptor like-receptor 1 receptor ligands useful e.g. for treating anxiety, depression, epilepsy, senile dementia, withdrawal symptoms or especially pain

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002090317A1 (en) 2001-05-09 2002-11-14 Grünenthal GmbH Substituted cyclohexane-1,4-diamine derivatives
US20040229872A1 (en) 2001-05-09 2004-11-18 Gruenenthal Gmbh Substituted cyclohexane-1,4-diamine compounds with anti-diarrhea and peripheral analgesic activity
US20030229119A1 (en) 2002-02-22 2003-12-11 Kym Philip R. Antagonists of melanin concentrating hormone effects on the melanin concetrating hormone receptor

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110059999A1 (en) * 2008-03-27 2011-03-10 Grünenthal GmbH Hydroxymethylcyclohexylamines
US8288406B2 (en) 2008-03-27 2012-10-16 Gruenenthal Gmbh Hydroxymethylcyclohexylamines

Also Published As

Publication number Publication date
JP5037337B2 (en) 2012-09-26
EP1745010B1 (en) 2009-08-05
CY1109569T1 (en) 2014-08-13
ES2333026T3 (en) 2010-02-16
EP1745010A1 (en) 2007-01-24
ATE438617T1 (en) 2009-08-15
WO2005110974A1 (en) 2005-11-24
CA2566297C (en) 2012-10-30
DK1745010T3 (en) 2009-12-07
PT1745010E (en) 2009-11-10
DE502005007850D1 (en) 2009-09-17
SI1745010T1 (en) 2010-01-29
CA2566297A1 (en) 2005-11-24
JP2007536323A (en) 2007-12-13
PL1745010T3 (en) 2010-01-29
DE102004023522A1 (en) 2005-12-01
US20070112007A1 (en) 2007-05-17

Similar Documents

Publication Publication Date Title
US8093272B2 (en) Heteroaryl substituted cyclohexyl-1,4-diamine compounds
US8017630B2 (en) Cyclohexylacetic acid compounds
US7476763B2 (en) Oxo-substituted cyclohexyl-1,4-diamine compounds
US8088763B2 (en) Cyclohexyl-1, 4-diamine compounds
US7439394B2 (en) Cyclohexyl-1,4-diamine compounds
US7786328B2 (en) Cyclohexyl-1,4-diamine compounds
US7241802B2 (en) Substituted cyclohexylcarboxylic acid amide compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: GRUENENTHAL GMBH,GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SUNDERMANN, CORINNA;SUNDERMANN, BERND;REEL/FRAME:018822/0407

Effective date: 20070111

Owner name: GRUENENTHAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SUNDERMANN, CORINNA;SUNDERMANN, BERND;REEL/FRAME:018822/0407

Effective date: 20070111

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20200103

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载